Abstract
The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (http://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
1.
Conflict of interest
The authors state that there are no conflicts of interest to disclose.
Overview
G protein‐coupled receptors (GPCRs) are the largest class of membrane proteins in the human genome. The term "7TM receptor" is commonly used interchangeably with "GPCR", although there are some receptors with seven transmembrane domains that do not signal through G proteins. GPCRs share a common architecture, each consisting of a single polypeptide with an extracellular N‐terminus, an intracellular C‐terminus and seven hydrophobic transmembrane domains (TM1‐TM7) linked by three extracellular loops (ECL1‐ECL3) and three intracellular loops (ICL1‐ICL3). About 800 GPCRs have been identified in man, of which about half have sensory functions, mediating olfaction (˜400), taste (33), light perception (10) and pheromone signalling (5) [http://www.ncbi.nlm.nih.gov/pubmed/15034552?dopt=AbstractPlus]. The remaining 350 non‐sensory GPCRs mediate signalling by ligands that range in size from small molecules to peptides to large proteins; they are the targets for the majority of drugs in clinical usage [http://www.ncbi.nlm.nih.gov/pubmed/17139284?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24016212?dopt=AbstractPlus], although only a minority of these receptors are exploited therapeutically. The first classification scheme to be proposed for GPCRs [http://www.ncbi.nlm.nih.gov/pubmed/8081729?dopt=AbstractPlus] divided them, on the basic of sequence homology, into six classes. These classes and their prototype members were as follows: Class A (rhodopsin‐like), Class B (secretin receptor family), Class C (metabotropic glutamate), Class D (fungal mating pheromone receptors), Class E (cyclic AMP receptors) and Class F (frizzled/smoothened). Of these, classes D and E are not found in vertebrates. An alternative classification scheme "GRAFS" [http://www.ncbi.nlm.nih.gov/pubmed/15862553?dopt=AbstractPlus] divides vertebrate GPCRs into five classes, overlapping with the A‐F nomenclature, viz:
Glutamate family (http://www.guidetopharmacology.org/GRAC/GPCRListForward?class=C), which includes metabotropic glutamate receptors, a calcium‐sensing receptor and GABAB receptors, as well as three taste type 1 receptors and a family of pheromone receptors (V2 receptors) that are abundant in rodents but absent in man [http://www.ncbi.nlm.nih.gov/pubmed/15034552?dopt=AbstractPlus].
Rhodopsin family (http://www.guidetopharmacology.org/GRAC/GPCRListForward?class=A), which includes receptors for a wide variety of small molecules, neurotransmitters, peptides and hormones, together with olfactory receptors, visual pigments, taste type 2 receptors and five pheromone receptors (V1 receptors).
http://www.guidetopharmacology.org/GRAC/GPCRListForward?class=Adhesion GPCRs are phylogenetically related to class B receptors, from which they differ by possessing large extracellular N‐termini that are autoproteolytically cleaved from their 7TM domains at a conserved "GPCR proteolysis site" (GPS) which lies within a much larger (320 residue) "GPCR autoproteolysis‐inducing" (GAIN) domain, an evolutionary ancient mofif also found in polycystic kidney disease 1 (PKD1)‐like proteins, which has been suggested to be both required and sufficient for autoproteolysis [http://www.ncbi.nlm.nih.gov/pubmed/23850273?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/GPCRListForward?class=Frizzled consists of 10 Frizzled proteins (FZD(1‐10)) and Smoothened (SMO). The FZDs are activated by secreted lipoglycoproteins of the WNT family, whereas SMO is indirectly activated by the Hedgehog (HH) family of proteins acting on the transmembrane protein Patched (PTCH).
Secretin family, encoded by 15 genes in humans. The ligands for receptors in this family are polypeptide hormones of 27‐141 amino acid residues; nine of the mammalian receptors respond to ligands that are structurally related to one another (glucagon, glucagon‐like peptides (GLP‐1, GLP‐2), glucose‐dependent insulinotropic polypeptide (GIP), secretin, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase‐activating polypeptide (PACAP) and growth‐hormone‐releasing hormone (GHRH)) [http://www.ncbi.nlm.nih.gov/pubmed/11790261?dopt=AbstractPlus].
GPCR families
| Family | Class A | Class B (Secretin) | Class C (Glutamate) | Adhesion | Frizzled |
| Receptors with known ligands | 197 | 15 | 12 | 0 | 11 |
| Orphans | 87 (54)a | ‐ | 8 (1)a | 26 (6)a | 0 |
| Sensory (olfaction) | 390b,c | ‐ | ‐ | ‐ | ‐ |
| Sensory (vision) | 10d opsins | ‐ | ‐ | ‐ | ‐ |
| Sensory (taste) | 30c taste 2 | ‐ | 3c taste 1 | ‐ | ‐ |
| Sensory (pheromone) | 5c vomeronasal 1 | ‐ | ‐ | ‐ | ‐ |
| Total | 719 | 15 | 22 | 33 | 11 |
aNumbers in brackets refer to orphan receptors for which an endogenous ligand has been proposed in at least one publication, see [http://www.ncbi.nlm.nih.gov/pubmed/23686350?dopt=AbstractPlus]; b[http://www.ncbi.nlm.nih.gov/pubmed/19129093?dopt=AbstractPlus]; c[http://www.ncbi.nlm.nih.gov/pubmed/15034552?dopt=AbstractPlus]; d[http://www.ncbi.nlm.nih.gov/pubmed/15774036?dopt=AbstractPlus].
Much of our current understanding of the structure and function of GPCRs is the result of pioneering work on the visual pigment rhodopsin and on the β2 adrenoceptor, the latter culminating in the award of the 2012 Nobel Prize in chemistry to Robert Lefkowitz and Brian Kobilka [http://www.ncbi.nlm.nih.gov/pubmed/23650120?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23650015?dopt=AbstractPlus].
Pseudogenes
Below is a curated list of pseudogenes that in humans are non‐coding for receptor protein. In some cases these have a shared ancestry with genes that encode functional receptors in rats and mice.
https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:19240, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:16341, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4529, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:16291, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7959, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4513, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:31924, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:31925, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:19103, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:19106, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:19107, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:20615, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:20640, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:20641, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:20642, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:43898, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:43905, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:20616. A more detailed listing containg further information can be viewed http://www.guidetopharmacology.org/GRAC//DATA/GPCR_pseudogenes.xlsx.
Olfactory receptors
Olfactory receptors are also seven‐transmembrane spanning G protein‐coupled receptors, responsible for the detection of odorants. These are not currently included as they are not yet associated with extensive pharmacological data but are curated in the following databases: The gene list of olfactory receptors at https://www.genenames.org/cgi‐bin/genefamilies/set/141, and curated by https://genome.weizmann.ac.il/horde/ and https://senselab.med.yale.edu/ordb/.
Further reading on G protein‐coupled receptors
Kenakin T. (2018) Is the Quest for Signaling Bias Worth the Effort? Mol. Pharmacol. 93: 266‐269 [https://www.ncbi.nlm.nih.gov/pubmed/29348268?dopt=AbstractPlus]
Michel MC et al. (2018) Biased Agonism in Drug Discovery‐Is It Too Soon to Choose a Path? Mol. Pharmacol. 93: 259‐265 [https://www.ncbi.nlm.nih.gov/pubmed/29326242?dopt=AbstractPlus]
Roth BL et al. (2017) Discovery of new GPCR ligands to illuminate new biology. Nat. Chem. Biol. 13: 1143‐1151 [https://www.ncbi.nlm.nih.gov/pubmed/29045379?dopt=AbstractPlus]
Sriram K et al. (2018) G Protein‐Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Mol. Pharmacol. 93: 251‐258 [https://www.ncbi.nlm.nih.gov/pubmed/29298813?dopt=AbstractPlus]
Family structure
S23 Orphan and other 7TM receptors
– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=706
–http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=975
S36 5‐Hydroxytryptamine receptors
S39 Acetylcholine receptors (muscarinic)
S67 Complement peptide receptors
S68 Corticotropin‐releasing factor receptors
S72 G protein‐coupled estrogen receptor
S81 Glycoprotein hormone receptors
S82 Gonadotrophin‐releasing hormone receptors
S86 Hydroxycarboxylic acid receptors
S89 Lysophospholipid (LPA) receptors
S90 Lysophospholipid (S1P) receptors
S92 Melanin‐concentrating hormone receptors
S95 Metabotropic glutamate receptors
S99 Neuropeptide FF/neuropeptide AF receptors
S101 Neuropeptide W/neuropeptide B receptors
S110 Parathyroid hormone receptors
S111 Platelet‐activating factor receptor
S113 Prolactin‐releasing peptide receptor
S116 Proteinase‐activated receptors
S118 Relaxin family peptide receptors
S123 Thyrotropin‐releasing hormone receptors
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=115
Overview
This set contains ’orphan’ G protein coupled receptors where the endogenous ligand(s) is not known, and other 7TM receptors.
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=16
Overview
Table 1 lists a number of putative GPCRs identified by NC‐IUPHAR[http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [http://www.ncbi.nlm.nih.gov/pubmed/23686350?dopt=AbstractPlus]. The GPCRs in Table 1 are all Class A, rhodopsin‐like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as‐yet unidentified endogenous ligands.
Table 1
Class A orphan GPCRs with putative endogenous ligands
In addition the orphan receptors http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=89, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=109 and http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=126 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=114).
Further reading on Class A Orphans
McNeil BD et al. (2015) Identification of a mast‐cell‐specific receptor crucial for pseudo‐allergic drug reactions. Nature 519: 237–41 [https://www.ncbi.nlm.nih.gov/pubmed/25517090?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=18
Overview
This set contains class C ’orphan’ G protein coupled receptors where the endogenous ligand(s) is not known.
Further reading on Class C Orphans
Harpse K et al. (2017) Structural insight to mutation effects uncover a common allosteric site in class C GPCRs. Bioinformatics 33: 1116–1120 [https://www.ncbi.nlm.nih.gov/pubmed/28011766?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=116
Overview
Whilst the taste of acid and salty foods appear to be sensed by regulation of ion channel activity, bitter, sweet and umami tastes are sensed by specialised GPCR. Two classes of taste GPCR have been identified, T1R and T2R, which are similar in sequence and structure to Class C and Class A GPCR, respectively. Activation of taste receptors appears to involve gustducin‐ (Gαt3) and Gα14‐mediated signalling, although the precise mechanisms remain obscure. Gene disruption studies suggest the involvement of PLCβ2 [http://www.ncbi.nlm.nih.gov/pubmed/12581520?dopt=AbstractPlus], TRPM5 [http://www.ncbi.nlm.nih.gov/pubmed/12581520?dopt=AbstractPlus] and IP3 [http://www.ncbi.nlm.nih.gov/pubmed/17925404?dopt=AbstractPlus] receptors in postreceptor signalling of taste receptors. Although predominantly associated with the oral cavity, taste receptors are also located elsewhere, including further down the gastrointestinal system, in the lungs and in the brain.
Sweet/Umami
T1R3 acts as an obligate partner in T1R1/T1R3 and T1R2/T1R3 heterodimers, which sense umami or sweet, respectively. T1R1/T1R3 heterodimers respond to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1369 and may be positively allosterically modulated by 5’‐nucleoside monophosphates, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5123 [http://www.ncbi.nlm.nih.gov/pubmed/12013525?dopt=AbstractPlus]. T1R2/T1R3 heterodimers respond to sugars, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5411, and artificial sweeteners, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5432 [http://www.ncbi.nlm.nih.gov/pubmed/11509186?dopt=AbstractPlus].
Comments
Positive allosteric modulators of T1R2/T1R3 have been reported [2363]. Such compounds enhance the sweet taste of sucrose mediated by these receptors, but are tasteless on their own.
Further reading on Taste 1 receptors
Palmer RK. (2019) A Pharmacological Perspective on the Study of Taste. Pharmacol. Rev. 71: 20–48 [https://www.ncbi.nlm.nih.gov/pubmed/30559245?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=117
G protein‐coupled receptors → Orphan and other 7TM receptors → Taste 2 receptors
Overview
The composition and stoichiometry of bitter taste receptors is not yet established. Bitter receptors appear to separate into two groups, with very restricted ligand specificity or much broader responsiveness. For example, T2R5 responded to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5433, but not 10 other bitter compounds [http://www.ncbi.nlm.nih.gov/pubmed/10761935?dopt=AbstractPlus], while T2R14 responded to at least eight different bitter tastants, including (‐)‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5344‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5344 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2291 [http://www.ncbi.nlm.nih.gov/pubmed/15178431?dopt=AbstractPlus].
Specialist database http://bitterdb.agri.huji.ac.il/dbbitter.php contains additional information on bitter compounds and receptors [http://www.ncbi.nlm.nih.gov/pubmed/21940398?dopt=AbstractPlus].
Further reading on Taste 2 receptors
Palmer RK. (2019) A Pharmacological Perspective on the Study of Taste. Pharmacol. Rev. 71: 20–48 [https://www.ncbi.nlm.nih.gov/pubmed/30559245?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=113
Further reading on Orphan and other 7TM receptors
Davenport AP et al. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein‐coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol. Rev. 65: 967–86 [https://www.ncbi.nlm.nih.gov/pubmed/23686350?dopt=AbstractPlus]
Gilissen J et al. (2016) Insight into SUCNR1 (GPR91) structure and function. Pharmacol. Ther. 159: 56–65 [https://www.ncbi.nlm.nih.gov/pubmed/26808164?dopt=AbstractPlus]
Insel PA et al. (2015) G Protein‐Coupled Receptor (GPCR) Expression in Native Cells: “Novel” endoGPCRs as Physiologic Regulators and Therapeutic Targets. Mol. Pharmacol. 88: 181‐7 [https://www.ncbi.nlm.nih.gov/pubmed/25737495?dopt=AbstractPlus]
Khan MZ et al. (2017) Neuro‐psychopharmacological perspective of Orphan receptors of Rhodopsin (class A) family of G protein‐coupled receptors. Psychopharmacology (Berl.) 234: 1181‐1207 [https://www.ncbi.nlm.nih.gov/pubmed/28289782?dopt=AbstractPlus]
Mackenzie AE et al. (2017) The emerging pharmacology and function of GPR35 in the nervous system. Neuropharmacology 113: 661–671 [https://www.ncbi.nlm.nih.gov/pubmed/26232640?dopt=AbstractPlus]
Ngo T et al. (2016) Identifying ligands at orphan GPCRs: current status using structure‐based approaches. Br. J. Pharmacol. 173: 2934‐51 [https://www.ncbi.nlm.nih.gov/pubmed/26837045?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1
Overview
5‐HT receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on 5‐HT receptors [http://www.ncbi.nlm.nih.gov/pubmed/7938165?dopt=AbstractPlus] and subsequently revised [http://www.ncbi.nlm.nih.gov/pubmed/8936345?dopt=AbstractPlus]) are, with the exception of the ionotropic 5‐HT3 class, GPCRs where the endogenous agonist is http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5. The diversity of metabotropic 5‐HT receptors is increased by alternative splicing that produces isoforms of the 5‐HT2A (non‐functional), 5‐HT2C (non‐functional), 5‐HT4, 5‐HT6 (non‐functional) and 5‐HT7 receptors. Unique amongst the GPCRs, RNA editing produces 5‐HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology [http://www.ncbi.nlm.nih.gov/pubmed/16896947?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18554725?dopt=AbstractPlus]. Most 5‐HT receptors (except 5‐ht1e and 5‐ht5b) play specific roles mediating functional responses in different tissues (reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/19086344?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17703282?dopt=AbstractPlus]).
Comments
Tabulated pK i and K D values refer to binding to human 5‐HT receptors unless indicated otherwise. The nomenclature of 5‐HT1B/5‐HT1D receptors has been revised [http://www.ncbi.nlm.nih.gov/pubmed/8936345?dopt=AbstractPlus]. Only the non‐rodent form of the receptor was previously called 5‐HT1D: the human 5‐HT1B receptor (tabulated) displays a different pharmacology to the rodent forms of the receptor due to Thr335 of the human sequence being replaced by Asn in rodent receptors [http://www.ncbi.nlm.nih.gov/pubmed/18571247?dopt=AbstractPlus]. Wang et al. (2013) report X‐ray structures which reveal the binding modality of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=149 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=121 (DHE) to the 5‐HT1B receptor in comparison with the structure of the 5HT2B receptor [http://www.ncbi.nlm.nih.gov/pubmed/23519210?dopt=AbstractPlus]; some of these drugs adopt rather different conformations depending on the target receptor [http://www.ncbi.nlm.nih.gov/pubmed/29398112?dopt=AbstractPlus]. Various 5‐HT receptors have multiple partners in addition to G proteins, which may affect function and pharmacology [http://www.ncbi.nlm.nih.gov/pubmed/21777185?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3226 is a selective antagonist of the rodent 5‐HT1B receptor. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5434 (LSD) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=88 bind with high affinity to dopamine D4 and histamine H1 receptors respectively, and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=88 is a potent α1 adrenoceptor antagonist, in addition to blocking 5‐HT2A receptors. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=139 (LSD) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=149 show a strong preference for arrestin recruitment over G protein coupling at the 5‐HT2B receptor, with no such preference evident at 5‐HT1B receptors, and they also antagonise 5‐HT7A receptors [http://www.ncbi.nlm.nih.gov/pubmed/23519215?dopt=AbstractPlus]. DHE (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=282), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=48 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=37 also show significant preference for arrestin recruitment over G protein coupling at 5‐HT2B receptors [http://www.ncbi.nlm.nih.gov/pubmed/23519215?dopt=AbstractPlus]. The 5‐HT2B (and other 5‐HT) receptors interact with immunocompetent cells [http://www.ncbi.nlm.nih.gov/pubmed/28265714?dopt=AbstractPlus]. The serotonin antagonist http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=206 was key to the discovery of the 5HT2C receptor [http://www.ncbi.nlm.nih.gov/pubmed/6519175?dopt=AbstractPlus], initially known as 5‐HT1C [http://www.ncbi.nlm.nih.gov/pubmed/28806488?dopt=AbstractPlus]. The human 5‐HT5A receptor may couple to several signal transduction pathways when stably expressed in C6 glioma cells [http://www.ncbi.nlm.nih.gov/pubmed/12558985?dopt=AbstractPlus] and rodent prefrontal cortex (layer V pyramidal neurons) [http://www.ncbi.nlm.nih.gov/pubmed/22539842?dopt=AbstractPlus]. The human orthologue of the mouse 5‐ht5b receptor is non‐functional (stop codons); the 5‐ht1e receptor has not been cloned from mouse, or rat, impeding definition of its function [http://www.ncbi.nlm.nih.gov/pubmed/18571247?dopt=AbstractPlus]. In addition to accepted receptors, an ’orphan’ receptor, unofficially termed5‐HT1P, has been described [http://www.ncbi.nlm.nih.gov/pubmed/10429737?dopt=AbstractPlus].
Further reading on 5‐Hydroxytryptamine receptors
Bockaert J et al. (2011) 5‐HT(4) receptors, a place in the sun: act two. Curr Opin Pharmacol 11: 87‐93 [https://www.ncbi.nlm.nih.gov/pubmed/21342787?dopt=AbstractPlus]
Hayes DJ et al. (2011) 5‐HT receptors and reward‐related behaviour: a review. Neurosci Biobehav Rev 35: 1419‐49 [https://www.ncbi.nlm.nih.gov/pubmed/21402098?dopt=AbstractPlus]
Hoyer D et al. (1994) International Union of Pharmacology classification of receptors for 5hydroxytryptamine (Serotonin). Pharmacol. Rev. 46: 157‐203 [https://www.ncbi.nlm.nih.gov/pubmed/7938165?dopt=AbstractPlus]
Leopoldo M et al. (2011)Serotonin 5‐HT7 receptor agents: Structure‐activity relationships and potential therapeutic applications in central nervous system disorders. Pharmacol. Ther. 129: 120‐48 [https://www.ncbi.nlm.nih.gov/pubmed/20923682?dopt=AbstractPlus]
Meltzer HY et al. (2011) The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 11: 59‐67 [https://www.ncbi.nlm.nih.gov/pubmed/21420906?dopt=AbstractPlus]
Roberts AJ et al. (2012) The 5‐HT(7) receptor in learning and memory. Hippocampus 22: 762‐71 [https://www.ncbi.nlm.nih.gov/pubmed/21484935?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=2
Overview
Muscarinic acetylcholine receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [http://www.ncbi.nlm.nih.gov/pubmed/9647869?dopt=AbstractPlus]) are GPCRs of the Class A, rhodopsin‐like family where the endogenous agonist is http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=294. In addition to the agents listed in the table, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=289, its structural analogues http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=334 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3271, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=333, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3258 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5435 have been described as functionally selective agonists of the M1 receptor subtype via binding in a mode distinct from that utilized by non‐selective agonists [http://www.ncbi.nlm.nih.gov/pubmed/20413650?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18842902?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18454168?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16207821?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17525129?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20684563?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16959945?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12021390?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/14595031?dopt=AbstractPlus]. There are two pharmacologically characterised allosteric sites on muscarinic receptors, one defined by it binding http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=356, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=347 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=342, and the other defined by the binding of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=337, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=340, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=339 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=346 [http://www.ncbi.nlm.nih.gov/pubmed/10860942?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12435818?dopt=AbstractPlus].
Comments
The crystal structures of the M1‐M4 receptor subtypes have been reported [http://www.ncbi.nlm.nih.gov/pubmed/22278061?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26958838?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22358838?dopt=AbstractPlus]. Direct activation via an allosteric site has been reported for M1 receptors (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5436, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9228) and M4 receptors (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3262) [http://www.ncbi.nlm.nih.gov/pubmed/27275946?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21300722?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19940843?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19717450?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20406819?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18628403?dopt=AbstractPlus]. The allosteric site for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=356 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=347 on M2 receptors can be labelled by [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=364 [http://www.ncbi.nlm.nih.gov/pubmed/12815174?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=290 is a functionally selective partial agonist that appears to interact in a bitopic mode with both the orthosteric and an allosteric site on the M2 muscarinic receptor [http://www.ncbi.nlm.nih.gov/pubmed/18723515?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3255, hybrid 1 and hybrid 2, are multivalent (bitopic) ligands that also achieve selectivity for M2 receptors by binding both to the orthosteric and a nearby allosteric site [http://www.ncbi.nlm.nih.gov/pubmed/18842964?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17478612?dopt=AbstractPlus].
Although numerous ligands for muscarinic acetylcholine receptors have been described, relatively few selective antagonists have been described, so it is common to assess the rank order of affinity of a number of antagonists of limited selectivity (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=307, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=321, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=328) in order to identify the involvement of particular subtypes. It should be noted that the measured affinities of antagonists (and agonists) in radioligand binding studies are sensitive to ionic strength and can increase over 10‐fold at low ionic strength compared to their values at physiological ionic strengths [http://www.ncbi.nlm.nih.gov/pubmed/497538?dopt=AbstractPlus].
Further reading on Acetylcholine receptors (muscarinic)
Burger WAC et al. (2018) Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors. J Gen Physiol 150: 1360‐1372 [https://www.ncbi.nlm.nih.gov/pubmed/30190312?dopt=AbstractPlus]
Caulfield MP et al. (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50: 279‐290 [https://www.ncbi.nlm.nih.gov/pubmed/9647869?dopt=AbstractPlus]
Eglen RM. (2012) Overview of muscarinic receptor subtypes. Handb Exp Pharmacol 3‐28 [https://www.ncbi.nlm.nih.gov/pubmed/22222692?dopt=AbstractPlus]
Kruse AC et al. (2014) Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov 13: 549‐60 [https://www.ncbi.nlm.nih.gov/pubmed/24903776?dopt=AbstractPlus]
Leach K et al. (2012) Structure‐function studies of muscarinic acetylcholine receptors. Handb Exp Pharmacol 29‐48 [https://www.ncbi.nlm.nih.gov/pubmed/22222693?dopt=AbstractPlus]
Valant C et al. (2012) The best of both worlds? Bitopic orthosteric/allosteric ligands of g proteincoupled receptors. Annu Rev Pharmacol Toxicol 52: 153‐78 [https://www.ncbi.nlm.nih.gov/pubmed/21910627?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=3
Overview
Adenosine receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Adenosine Receptors [http://www.ncbi.nlm.nih.gov/pubmed/11734617?dopt=AbstractPlus]) are activated by the endogenous ligand http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2844 (potentially http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4554 also at A3 receptors). Crystal structures for the antagonist‐bound [http://www.ncbi.nlm.nih.gov/pubmed/22220592?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18832607?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22798613?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/27312113?dopt=AbstractPlus], agonist‐bound [http://www.ncbi.nlm.nih.gov/pubmed/25762024?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21593763?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21393508?dopt=AbstractPlus] and G protein‐bound A2A adenosine receptors [http://www.ncbi.nlm.nih.gov/pubmed/27462812?dopt=AbstractPlus] have been described. The structures of an antagonist‐bound A1 receptor [http://www.ncbi.nlm.nih.gov/pubmed/28235198?dopt=AbstractPlus] and an adenosine‐bound A1 receptor‐Gi complex [http://www.ncbi.nlm.nih.gov/pubmed/29925945?dopt=AbstractPlus] have been resolved by cryo‐electronmicroscopy. Another structure of an antagonist‐bound A1 receptor obtained with X‐ray crystallography has also been reported [http://www.ncbi.nlm.nih.gov/pubmed/28712806?dopt=AbstractPlus].
Comments
Adenosine inhibits many intracellular ATP‐utilising enzymes, including adenylyl cyclase (P‐site). A pseudogene exists for the A2B adenosine receptor (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:265) with 79% identity to the A2B adenosine receptor cDNA coding sequence, but which is unable to encode a functional receptor [http://www.ncbi.nlm.nih.gov/pubmed/7558011?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=386 also exhibits antagonism at A2B receptors (pKi ca. 7,[http://www.ncbi.nlm.nih.gov/pubmed/8937736?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9459566?dopt=AbstractPlus]). Antagonists at A3 receptors exhibit marked species differences, such that only http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=474 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=470 are selective at the rat A3 receptor. In the absence of other adenosine receptors, [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=406 and [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=455 can also be used to label A2B receptors (KD ca. 30 and 60 nM respectively). [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=436 also binds to A1 receptors [http://www.ncbi.nlm.nih.gov/pubmed/9459566?dopt=AbstractPlus]. [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=424 is relatively selective for A2A receptors, but may also bind to other sites in cerebral cortex [http://www.ncbi.nlm.nih.gov/pubmed/8692280?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7566470?dopt=AbstractPlus]. [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=425 binds to other non‐receptor elements, which also recognise adenosine [http://www.ncbi.nlm.nih.gov/pubmed/8937447?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3279 has been described as a fluorescent antagonist for labelling A1 adenosine receptors in living cells, although activity at other adenosine receptors was not examined [http://www.ncbi.nlm.nih.gov/pubmed/15070776?dopt=AbstractPlus].
Further reading on Adenosine receptors
Borea PA et al. (2015) The A3 adenosine receptor: history and perspectives. Pharmacol Rev 67: 74‐102 [https://www.ncbi.nlm.nih.gov/pubmed/25387804?dopt=AbstractPlus]
Cronstein BN et al. (2017) Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nat Rev Rheumatol 13: 41‐51 [https://www.ncbi.nlm.nih.gov/pubmed/27829671?dopt=AbstractPlus]
Fredholm BB et al. (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors–an update. Pharmacol Rev 63: 1‐34 [https://www.ncbi.nlm.nih.gov/pubmed/21303899?dopt=AbstractPlus]
Guo D et al. (2017) Kinetic Aspects of the Interaction between Ligand and G Protein‐Coupled Receptor: The Case of the Adenosine Receptors. Chem Rev 117: 38‐66 [https://www.ncbi.nlm.nih.gov/pubmed/27088232?dopt=AbstractPlus]
Göblyös A et al. (2011) Allosteric modulation of adenosine receptors. Biochim Biophys Acta 1808: 1309‐18 [https://www.ncbi.nlm.nih.gov/pubmed/20599682?dopt=AbstractPlus]
Lasley RD. (2011) Adenosine receptors and membrane microdomains. Biochim Biophys Acta 1808: 1284‐9 [https://www.ncbi.nlm.nih.gov/pubmed/20888790?dopt=AbstractPlus]
Mundell S et al. (2011) Adenosine receptor desensitization and trafficking. Biochim Biophys Acta 1808: 1319‐28 [https://www.ncbi.nlm.nih.gov/pubmed/20550943?dopt=AbstractPlus]
Vecchio EA et al. (2018) New paradigms in adenosine receptor pharmacology: allostery, oligomerization and biased agonism. Br J Pharmacol 175: 4036‐4046 [https://www.ncbi.nlm.nih.gov/pubmed/29679502?dopt=AbstractPlus]
Wei CJ etal. (2011)Normaland abnormalfunctions ofadenosine receptors inthecentral nervous system revealed by genetic knockout studies. Biochim Biophys Acta 1808: 1358‐79[https://www.ncbi.nlm.nih.gov/pubmed/21185258?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=17
Overview
Adhesion GPCRs are structurally identified on the basis of a large extracellular region, similar to the Class B GPCR, but which is linked to the 7TM region by a GPCR autoproteolysisinducing (GAIN) domain [http://www.ncbi.nlm.nih.gov/pubmed/22333914?dopt=AbstractPlus] containing a GPCR proteolytic site. The N‐terminus often shares structural homology with adhesive domains (e.g. cadherins, immunolobulin, lectins) facilitating inter‐ and matricellular interactions and leading to the term adhesion GPCR [http://www.ncbi.nlm.nih.gov/pubmed/12761335?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18789697?dopt=AbstractPlus]. Several receptors have been suggested to function as mechanosensors [http://www.ncbi.nlm.nih.gov/pubmed/26841242?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25695270?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25937282?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26499266?dopt=AbstractPlus]. The nomenclature of these receptors was revised in 2015 as recommended by NC‐IUPHAR and the Adhesion GPCR Consortium [http://www.ncbi.nlm.nih.gov/pubmed/25713288?dopt=AbstractPlus].
Further reading on Adhesion Class GPCRs
Hamann J et al. (2015) International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein‐coupled receptors. Pharmacol Rev 67: 338‐67 [https://www.ncbi.nlm.nih.gov/pubmed/25713288?dopt=AbstractPlus]
Langenhan T et al. (2013) Sticky signaling–adhesion class G protein‐coupled receptors take the stage. Sci Signal 6: re3 [https://www.ncbi.nlm.nih.gov/pubmed/23695165?dopt=AbstractPlus]
Liebscher I et al. (2016) Tethered Agonism: A Common Activation Mechanism of Adhesion GPCRs. Handb Exp Pharmacol 234: 111‐125 [https://www.ncbi.nlm.nih.gov/pubmed/27832486?dopt=AbstractPlus]
Monk KR et al. (2015) Adhesion G Protein‐Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms. Mol Pharmacol 88: 617‐23 [https://www.ncbi.nlm.nih.gov/pubmed/25956432?dopt=AbstractPlus]
Purcell RH et al. (2018) Adhesion G Protein‐Coupled Receptors as Drug Targets. Annu Rev Pharmacol Toxicol 58: 429‐449 [https://www.ncbi.nlm.nih.gov/pubmed/28968187?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=4
Overview
The nomenclature of the Adrenoceptors has been agreed by the NC‐IUPHAR Subcommittee on Adrenoceptors [http://www.ncbi.nlm.nih.gov/pubmed/7938162?dopt=AbstractPlus], see also [http://www.ncbi.nlm.nih.gov/pubmed/7568329?dopt=AbstractPlus].
Adrenoceptors, α1
α1‐Adrenoceptors are activated by the endogenous agonists (‐)‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=479 and (‐)‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=505. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=485, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=483 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=515 are agonists and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=503 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=515 antagonists considered selective for α1‐ relative to α2‐adrenoceptors. [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5385 and [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=482 (BE2254) are relatively selective radioligands. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=487 also has high affinity for L‐type Ca2+ channels. Fluorescent derivatives of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=503 (Bodipy PLprazosin‐ QAPB) are used to examine cellular localisation of α1‐adrenoceptors. Selective α1‐adrenoceptor agonists are used as nasal decongestants; antagonists to treat hypertension (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7170, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7170) and benign prostatic hyperplasia (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7109, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=488). The α1‐ and β2‐adrenoceptor antagonist http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=551 is used to treat congestive heart failure, although the contribution of α1‐adrenoceptor blockade to the therapeutic effect is unclear. Several anti‐depressants and anti‐psychotic drugs are α1‐adrenoceptor antagonists contributing to side effects such as orthostatic hypotension and extrapyramidal effects.
Comments
The α1C‐adrenoceptor corresponds to the pharmacologically defined α1A‐adrenoceptor [http://www.ncbi.nlm.nih.gov/pubmed/7568329?dopt=AbstractPlus]. Some tissues possess α1A‐adrenoceptors (α1L‐adrenoceptors [http://www.ncbi.nlm.nih.gov/pubmed/9249248?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17162094?dopt=AbstractPlus]) that display relatively low affinity in functional and binding assays for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=503 indicative of different receptor states or locations. α1A‐adrenoceptor C‐terminal splice variants form homo‐ and heterodimers, but fail to generate a functional α1L‐adrenoceptor [http://www.ncbi.nlm.nih.gov/pubmed/15266013?dopt=AbstractPlus]. α1D‐Adrenoceptors form heterodimers with α1B‐ or β2‐adrenoceptors that show increased cell‐surface expression [http://www.ncbi.nlm.nih.gov/pubmed/15615865?dopt=AbstractPlus]. Recombinant α1D‐adrenoceptors have been shown in some heterologous systems to be mainly located intracellularly but cell‐surface localization is encouraged by truncation of the Nterminus, or by co‐expression of α1B‐ or β2‐adrenoceptors [http://www.ncbi.nlm.nih.gov/pubmed/14718583?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/14718583?dopt=AbstractPlus]. In blood vessels all three α1‐adrenoceptor subtypes are located on the surface and intracellularly [http://www.ncbi.nlm.nih.gov/pubmed/19572943?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19888965?dopt=AbstractPlus]. Signalling is predominantly via Gq/11 butα1‐adrenoceptors also couple toGi/o, Gs and G12/13. Several α1A‐adrenoceptor agonists display ligand directed signalling bias relative to noradrenaline [http://www.ncbi.nlm.nih.gov/pubmed/20978120?dopt=AbstractPlus]. There are also differences between subtypes in coupling efficiency to different pathways. In vascular smooth muscle, the potency of agonists is related to the predominant subtype, α1D‐ conveying greater agonist sensitivity than α1A‐adrenoceptors [http://www.ncbi.nlm.nih.gov/pubmed/23373597?dopt=AbstractPlus].
Adrenoceptors, α2
α2‐Adrenoceptors are activated by (‐)‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=479 and with lower potency by (‐)‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=505. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=520 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5442 are agonists and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=136 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=102 antagonists selective for α2‐ relative to α1‐adrenoceptors. [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=223, [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5386 and [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=528 are relatively selective radioligands. There is species variation in the pharmacology of the α2A‐adrenoceptor. Multiple mutations of α2‐adrenoceptors have been described, some associated with alterations in function. Presynaptic α2‐adrenoceptors regulate many functions in the nervous system. The α2‐adrenoceptor agonists http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=516, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5443 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=520 affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=516 is an anti‐hypertensive and counteracts opioid withdrawal. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=521 (also http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=523) is used as a sedative and analgesic in human and veterinary medicine with sympatholytic and anxiolytic properties. The α2‐adrenoceptor antagonist http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=102 has been used to treat erectile dysfunction and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7241 as an anti‐depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells.
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=524 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=503 show selectivity for α2B‐ and α2C‐adrenoceptors over α2A‐adrenoceptors.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=124 is a reduced efficacy imidazoline agonist but also binds to non‐GPCR binding sites for imidazolines, classified as I1, I2 and I3 sites [http://www.ncbi.nlm.nih.gov/pubmed/15224384?dopt=AbstractPlus]; catecholamines have a low affinity, while rilmenidine and moxonidine are selective ligands evoking hypotensive effects in vivo. I1‐imidazoline receptors cause central inhibition of sympathetic tone, I2‐imidazoline receptors are an allosteric binding site on monoamine oxidase B, and I3‐imidazoline receptors regulate insulin secretion from pancreatic β‐cells. α2A‐adrenoceptor stimulation reduces insulin secretion from β‐islets [http://www.ncbi.nlm.nih.gov/pubmed/22645144?dopt=AbstractPlus], with a polymorphism in the 5’‐UTR of the ADRA2A gene being associated with increased receptor expression in β‐islets and heightened susceptibility to diabetes [http://www.ncbi.nlm.nih.gov/pubmed/19965390?dopt=AbstractPlus]. α2A‐ and α2C‐adrenoceptors form homodimers [http://www.ncbi.nlm.nih.gov/pubmed/16605244?dopt=AbstractPlus]. Heterodimers between α2A‐ and either the α2C‐adrenoceptor or μ opioid peptide receptor exhibit altered signalling and trafficking properties compared to the individual receptors [http://www.ncbi.nlm.nih.gov/pubmed/16605244?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19126537?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18193048?dopt=AbstractPlus]. Signalling by α2‐adrenoceptors is primarily via Gi/o, although the α2A‐adrenoceptor also couples to Gs [http://www.ncbi.nlm.nih.gov/pubmed/7559592?dopt=AbstractPlus]. Imidazoline compounds display bias relative to each other at the α2A‐adrenoceptor [http://www.ncbi.nlm.nih.gov/pubmed/12649300?dopt=AbstractPlus]. The noradrenaline reuptake inhibitor desipramine acts directly on the α2A‐adrenoceptor to promote internalisation via recruitment of arrestin [http://www.ncbi.nlm.nih.gov/pubmed/21859713?dopt=AbstractPlus].
Adrenoceptors, β
β‐Adrenoceptors are activated by the endogenous agonists (‐)‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=479 and (‐)‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=505. Isoprenaline is selective for β‐adrenoceptors relative to α1‐ and α2‐adrenoceptors, while http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=564 (pKi 8.2‐9.2) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=132 (pKi 10.011.0) are relatively β1 and β2 adrenoceptor‐selective antagonists. (‐)‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=505, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=538 and (‐)‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5571 show selectivity for β1‐ relative to β2‐adrenoceptors. Pharmacological differences exist between human and mouse β3‐adrenoceptors, and the ’rodent selective’ agonists http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=567 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3462 have low efficacy at the human β3‐adrenoceptor whereas http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=532 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3931 activate human β3‐adrenoceptors [88]. β3‐Adrenoceptors are resistant to blockade by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=564, but can be blocked by high concentrations of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=550. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=547 has reasonably high affinity at β3‐adrenoceptors, but does not discriminate well between the three β‐ subtypes whereas http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3931 is more selective. [125I]‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=132, [125I]‐hydroxy benzylpindolol and [3H]‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=563 are high affinity radioligands that label β1‐ and β2‐ adrenoceptors and β3‐adrenoceptors can be labelled with higher concentrations (nM) of [125I]‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=132 together with β1‐ and β2‐adrenoceptor antagonists. [3H]‐L748337 is a β3‐selective radioligand [http://www.ncbi.nlm.nih.gov/pubmed/24183974?dopt=AbstractPlus]. Fluorescent ligands such as BODIPY‐TMR‐CGP12177 can be used to track βadrenoceptors at the cellular level [8]. Somewhat selective β1adrenoceptor agonists (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=534, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=535) are used short term to treat cardiogenic shock but, chronically, reduce survival. β1‐Adrenoceptor‐preferring antagonists areused totreathypertension (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=548, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=549, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7129, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=553 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7246), cardiac arrhythmias (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=548, bisoprolol, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7178) and cardiac failure (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=553, nebivolol). Cardiac failure is also treated with carvedilol that blocks β1‐ and β2‐adrenoceptors, as well as α1‐adrenoceptors. Short (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=558, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=560) and long (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3465, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=559) acting β2‐adrenoceptor‐selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β‐adrenoceptor antagonists (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=564) block both β1‐ and β2‐adrenoceptors and there are no β2adrenoceptor‐selective antagonists used therapeutically. The β3‐adrenoceptor agonist http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7445 is used to control overactive bladder syndrome.
Comments
[http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=562 can be used to define β1‐ or β2adrenoceptors when conducted in the presence of a β1‐ or β2adrenoceptor‐selective antagonist. A fluorescent analogue of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=532 can be used to study β2‐adrenoceptors in living cells [http://www.ncbi.nlm.nih.gov/pubmed/12770928?dopt=AbstractPlus]. [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=562 at higher (nM) concentrations can be used to label β3‐adrenoceptors in systems with few if any other β‐adrenoceptor subtypes. The β3‐adrenoceptor has an intron in the coding region, but splice variants have only been described for the mouse [http://www.ncbi.nlm.nih.gov/pubmed/10455305?dopt=AbstractPlus], where the isoforms display different signalling characteristics [http://www.ncbi.nlm.nih.gov/pubmed/11959793?dopt=AbstractPlus]. There are 3 β‐adrenoceptors in turkey (termed the tβ, tβ3c and tβ4c) that have a pharmacology that differs from the human β‐adrenoceptors [http://www.ncbi.nlm.nih.gov/pubmed/21152092?dopt=AbstractPlus]. Numerous polymorphisms have been described for the β‐adrenoceptors; some are associated with signalling and trafficking, altered susceptibility to disease and/or altered responses to pharmacotherapy [http://www.ncbi.nlm.nih.gov/pubmed/15090197?dopt=AbstractPlus]. All β‐adrenoceptors couple to Gs (activating adenylyl cyclase and elevating cAMP levels), but also activate Gi and β‐arrestin‐mediated signalling. Many β1‐ and β2‐adrenoceptor antagonists are agonists at β3adrenoceptors (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3462 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=569). Many ‘antagonists’ of cAMP accumulation, for example http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=551 and bucindolol, weakly activate MAP kinase pathways [http://www.ncbi.nlm.nih.gov/pubmed/14645666?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20132209?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16901982?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18403719?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17717109?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18684840?dopt=AbstractPlus] and thus display ’protean agonism’. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=550 acts as a neutral antagonist in most systems so far examined. Agonists also display biased signalling at the β2‐adrenoceptor via Gs or arrestins [http://www.ncbi.nlm.nih.gov/pubmed/18086673?dopt=AbstractPlus]. X‐ray crystal structures have been described of the agonist bound [http://www.ncbi.nlm.nih.gov/pubmed/21228877?dopt=AbstractPlus] and antagonist bound forms of the β1[http://www.ncbi.nlm.nih.gov/pubmed/18594507?dopt=AbstractPlus], agonist‐bound [http://www.ncbi.nlm.nih.gov/pubmed/17962520?dopt=AbstractPlus] and antagonist‐bound forms of the β2‐adrenoceptor [http://www.ncbi.nlm.nih.gov/pubmed/21228869?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21228876?dopt=AbstractPlus], as well as a fully active agonistbound, Gs protein‐coupled β2‐adrenoceptor [http://www.ncbi.nlm.nih.gov/pubmed/21772288?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=551 and bucindolol bind to a site on the β1‐adrenoceptor involving contacts in TM2, 3, and 7 and extracellular loop 2 that may facilitate coupling to arrestins [http://www.ncbi.nlm.nih.gov/pubmed/18594507?dopt=AbstractPlus]. Compounds displaying arrestinbiased signalling at the β2‐adrenoceptor have a greater effect on the conformation of TM7, whereas full agonists for Gs coupling promote movement of TM5 and TM6 [http://www.ncbi.nlm.nih.gov/pubmed/22267580?dopt=AbstractPlus]. Recent studies using NMR spectroscopy demonstrate significant conformational flexibility in the β2‐adrenoceptor that is stabilized by both agonist and G proteins highlighting the dynamic nature of interactions with both ligand and downstreamsignalling partners [http://www.ncbi.nlm.nih.gov/pubmed/23721409?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25981665?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23374348?dopt=AbstractPlus]. Such flexibility likely has consequences for our understanding of biased agonism, and for the future therapeutic exploitation of this phenomenon.
Further reading on Adrenoceptors
Baker JG et al. (2011) Evolution of β‐blockers: from anti‐anginal drugs to ligand‐directed signalling. Trends Pharmacol. Sci. 32: 227‐34 [https://www.ncbi.nlm.nih.gov/pubmed/21429598?dopt=AbstractPlus]
Bylund DB et al. (1994) International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol. Rev. 46: 121‐136 [https://www.ncbi.nlm.nih.gov/pubmed/7938162?dopt=AbstractPlus]
Evans BA et al. (2010) Ligand‐directed signalling at beta‐adrenoceptors. Br. J. Pharmacol. 159: 1022‐38 [https://www.ncbi.nlm.nih.gov/pubmed/20132209?dopt=AbstractPlus]
Jensen BC et al. (2011) Alpha‐1‐adrenergic receptors: targets for agonist drugs to treat heart failure. J. Mol. Cell. Cardiol. 51: 518‐28 [https://www.ncbi.nlm.nih.gov/pubmed/21118696?dopt=AbstractPlus]
Kobilka BK. (2011) Structural insights into adrenergic receptor function and pharmacology. Trends Pharmacol. Sci. 32: 213‐8 [https://www.ncbi.nlm.nih.gov/pubmed/21414670?dopt=AbstractPlus]
Langer SZ. (2015) a2‐Adrenoceptors in the treatment of major neuropsychiatric disorders. Trends Pharmacol. Sci. 36: 196‐202 [https://www.ncbi.nlm.nih.gov/pubmed/25771972?dopt=AbstractPlus]
Michel MC et al. (2015) Selectivity of pharmacological tools: implications for use in cell physiology. A review in the theme: Cell signaling: proteins, pathways and mechanisms. Am. J. Physiol., Cell Physiol. 308: C505‐20 [https://www.ncbi.nlm.nih.gov/pubmed/25631871?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=6
Overview
The actions of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2504 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:333, http://www.uniprot.org/uniprot/P01019) (Ang II) are mediated by AT1 and AT2 receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Angiotensin receptors [http://www.ncbi.nlm.nih.gov/pubmed/10977869?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26315714?dopt=AbstractPlus]), which have around 30% sequence similarity. The decapeptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=583, http://www.uniprot.org/uniprot/P01019), the octapeptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2504, http://www.uniprot.org/uniprot/P01019) and the heptapeptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=585, http://www.uniprot.org/uniprot/P01019) are endogenous ligands. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=590, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=587, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=592, etc. are clinically used AT1 receptor blockers.
Comments
AT1 receptors are predominantly coupled to Gq/11, however they are also linked to arrestin recruitment and stimulate G protein‐independent arrestin signalling [http://www.ncbi.nlm.nih.gov/pubmed/20427692?dopt=AbstractPlus]. Most species express a single AGTR1 gene, but two related agtr1a and agtr1b receptor genes are expressed in rodents. The AT2 receptor counteracts several of the growth responses initiated by the AT1 receptors. The AT2 receptor is much less abundant than the AT1 receptor in adult tissues and is upregulated in pathological conditions. AT1 receptor antagonists bearing substituted 4‐phenylquinoline moieties have been synthesized, which bind to AT1 receptors with nanomolar affinity and are slightly more potent than http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=590 in functional studies [http://www.ncbi.nlm.nih.gov/pubmed/15115399?dopt=AbstractPlus]. The antagonist activity of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3944 at the AT2 receptor has also been reported [http://www.ncbi.nlm.nih.gov/pubmed/3071214?dopt=AbstractPlus]. The AT1 and bradykinin B2 receptors have been proposed to form a heterodimeric complex [http://www.ncbi.nlm.nih.gov/pubmed/10993080?dopt=AbstractPlus]. β‐Arrestin1 prevents AT1‐B2 receptor heteromerization[http://www.ncbi.nlm.nih.gov/pubmed/30503206?dopt=AbstractPlus]. There is also evidence for an AT4 receptor that specifically binds http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5368 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:333, http://www.uniprot.org/uniprot/P01019) and is located in the brain and kidney. An additional putative endogenous ligand for the AT4 receptor has been described (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5353 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4827, http://www.uniprot.org/uniprot/P68871), a globin decapeptide) [http://www.ncbi.nlm.nih.gov/pubmed/9166749?dopt=AbstractPlus].
Further reading on Angiotensin receptors
Asada H et al. (2018) Crystal structure of the human angiotensin II type 2 receptor bound to an angiotensin II analog. Nat. Struct. Mol. Biol. 25: 570‐576 [https://www.ncbi.nlm.nih.gov/pubmed/29967536?dopt=AbstractPlus]
Karnik SS et al. (2015) International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli [corrected]. Pharmacol. Rev. 67: 754‐819 [https://www.ncbi.nlm.nih.gov/pubmed/26315714?dopt=AbstractPlus]
Singh KD et al. (2019) Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of AT_1R Initiated by van der Waals Attraction. J Chem Inf Model 59: 373‐385 [https://www.ncbi.nlm.nih.gov/pubmed/30608150?dopt=AbstractPlus]
Wingler LM et al. (2019) Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations. Cell 176: 468‐478.e11 [https://www.ncbi.nlm.nih.gov/pubmed/30639099?dopt=AbstractPlus]
Wingler LM et al. (2019) Distinctive Activation Mechanism for Angiotensin Receptor Revealed by a Synthetic Nanobody. Cell 176: 479‐490.e12 [https://www.ncbi.nlm.nih.gov/pubmed/30639100?dopt=AbstractPlus]
Zhang H et al. (2015) Structure of the Angiotensin receptor revealed by serial femtosecond crystallography. Cell 161: 833‐44 [https://www.ncbi.nlm.nih.gov/pubmed/25913193?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=7
Overview
The apelin receptor (nomenclature as agreed by the NC‐IUPHAR Subcommittee on the apelin receptor [http://www.ncbi.nlm.nih.gov/pubmed/20605969?dopt=AbstractPlus]) responds to apelin, a 36 amino‐acid peptide derived initially from bovine stomach. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=606 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:16665, http://www.uniprot.org/uniprot/Q9ULZ1), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=605, http://www.uniprot.org/uniprot/Q9ULZ1) and [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=599]http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=599 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:16665, http://www.uniprot.org/uniprot/Q9ULZ1) are the predominant endogenous ligands which are cleaved from a 77 amino‐acid precursor peptide (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:16665 http://www.uniprot.org/uniprot/Q9ULZ1) by a so far unidentified enzymatic pathway [http://www.ncbi.nlm.nih.gov/pubmed/9792798?dopt=AbstractPlus]. A second family of peptides discovered independently and named Elabela [http://www.ncbi.nlm.nih.gov/pubmed/24316148?dopt=AbstractPlus] or Toddler, that has little sequence similarity to apelin, is present, and functional at the apelin receptor in the adult cardiovascular system [http://www.ncbi.nlm.nih.gov/pubmed/24407481?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/28137936?dopt=AbstractPlus]. Structure‐activity relationship Elabela analogues have been described [http://www.ncbi.nlm.nih.gov/pubmed/26986036?dopt=AbstractPlus].
Comments
Potency order determined for heterologously expressed human apelin receptor (pD 2 values range from 9.5 to 8.6). The apelin receptor may also act as a co‐receptor with CD4 for isolates of human immunodeficiency virus, with apelin blocking this function [http://www.ncbi.nlm.nih.gov/pubmed/11090199?dopt=AbstractPlus]. A modified apelin‐13 peptide, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5354) was reported to block the hypotensive response to apelin in rat in vivo [http://www.ncbi.nlm.nih.gov/pubmed/15486224?dopt=AbstractPlus], however, this peptide exhibits agonist activity in HEK293 cells stably expressing the recombinant apelin receptor [http://www.ncbi.nlm.nih.gov/pubmed/12939143?dopt=AbstractPlus]. The apelin receptor antagonist, MM54, was reported to suppress tumour growth and increase survival in an intracranial xenograft mouse model of glioblastoma [http://www.ncbi.nlm.nih.gov/pubmed/29053791?dopt=AbstractPlus].
Further reading on Apelin receptor
Cheng B et al. (2012) Neuroprotection of apelin and its signaling pathway. Peptides 37: 171‐3 [https://www.ncbi.nlm.nih.gov/pubmed/22820556?dopt=AbstractPlus]
Langelaan DN et al. (2009) Structural insight into G‐protein coupled receptor binding by apelin. Biochemistry 48: 537‐48 [https://www.ncbi.nlm.nih.gov/pubmed/19123778?dopt=AbstractPlus]
Mughal A et al. (2018) Vascular effects of apelin: Mechanisms and therapeutic potential. Pharmacol. Ther. 190: 139‐147 [https://www.ncbi.nlm.nih.gov/pubmed/29807055?dopt=AbstractPlus]
O’Carroll AM et al. (2013) The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis. J. Endocrinol. 219: R13‐35 [https://www.ncbi.nlm.nih.gov/pubmed/23943882?dopt=AbstractPlus]
Pitkin SL et al. (2010) International Union of Basic and Clinical Pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. Pharmacol. Rev. 62: 331‐42 [https://www.ncbi.nlm.nih.gov/pubmed/20605969?dopt=AbstractPlus]
Yang P et al. (2015) Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system. Trends Pharmacol. Sci. 36: 560‐7 [https://www.ncbi.nlm.nih.gov/pubmed/26143239?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=8
Overview
The bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2718. Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis.
Comments
The triterpenoid natural product http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3945 has also been reported to inhibit inflammatory signalling through the NFκB pathway [http://www.ncbi.nlm.nih.gov/pubmed/12960358?dopt=AbstractPlus]. Disruption of GPBA expression is reported to protect from cholesterol gallstone formation [http://www.ncbi.nlm.nih.gov/pubmed/16724960?dopt=AbstractPlus]. A new series of 5‐phenoxy‐1,3‐dimethyl‐1H‐pyrazole‐4‐carboxamides have been reported as highly potent agonists [http://www.ncbi.nlm.nih.gov/pubmed/23337601?dopt=AbstractPlus].
Further reading on Bile acid receptor
Duboc H et al. (2014) The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis 46: 302‐12 [https://www.ncbi.nlm.nih.gov/pubmed/24411485?dopt=AbstractPlus]
Lieu T et al. (2014) GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation. Br. J. Pharmacol. 171: 1156‐66 [https://www.ncbi.nlm.nih.gov/pubmed/24111923?dopt=AbstractPlus]
Lefebvre P et al. (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol. Rev. 89: 147‐91 [https://www.ncbi.nlm.nih.gov/pubmed/19126757?dopt=AbstractPlus]
van Nierop FS et al. (2017) Clinical relevance of the bile acid receptor TGR5 in metabolism. Lancet Diabetes Endocrinol 5: 224‐233 [https://www.ncbi.nlm.nih.gov/pubmed/27639537?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=9
Overview
Mammalian bombesin (Bn) receptors comprise 3 subtypes: BB1, BB2, BB3 (nomenclature recommended by the NC‐IUPHAR Subcommittee on bombesin receptors, [http://www.ncbi.nlm.nih.gov/pubmed/18055507?dopt=AbstractPlus]). BB1 and BB2 are activated by the endogenous ligands http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=612 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4605, http://www.uniprot.org/uniprot/P07492) (GRP), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=613 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7842, http://www.uniprot.org/uniprot/P08949) (NMB) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3582) (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4605, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4605). http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=616 is a tetradecapeptide, originally derived from amphibians. The three Bn receptor subtypes couple primarily to the Gq/11 and G12/13 family of G proteins [http://www.ncbi.nlm.nih.gov/pubmed/18055507?dopt=AbstractPlus]. Each of these receptors is widely distributed in the CNS and peripheral tissues [http://www.ncbi.nlm.nih.gov/pubmed/26066663?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18055507?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15726424?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25976083?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15203211?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22911445?dopt=AbstractPlus]. Activation of BB1 and BB2 receptors causes a wide range of physiological/pathophysiogical actions, including the stimulation of normal and neoplastic tissue growth, smoothmuscle contraction, feeding behavior, secretion and many central nervous system effects including regulation of circadian rhythm and mediation of pruritus [http://www.ncbi.nlm.nih.gov/pubmed/18055507?dopt=AbstractPlus, 991, 992, http://www.ncbi.nlm.nih.gov/pubmed/21042212?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15134870?dopt=AbstractPlus,http://www.ncbi.nlm.nih.gov/pubmed/25976083?dopt=AbstractPlus]. A physiological role for the BB3 receptor has yet to be fully defined although recently studies suggest an important role in glucose and insulin regulation, metabolic homeostasis, feeding, regulation of body temperature, obesity, diabetes mellitus and growth of normal/neoplastic tissues [http://www.ncbi.nlm.nih.gov/pubmed/26066663?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22157398?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9367152?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/27055378?dopt=AbstractPlus].
Comments
All three human subtypes may be activated by [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=632,http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=632‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=632,http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=632,http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=632]http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=632) [http://www.ncbi.nlm.nih.gov/pubmed/9325344?dopt=AbstractPlus]. [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3946,http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3946,http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3946,http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3946]http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3946) has more than 200‐fold selectivity for BB3 receptors over BB1 and BB2 [http://www.ncbi.nlm.nih.gov/pubmed/15102928?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15102928?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25976083?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26524625?dopt=AbstractPlus].
Further reading on Bombesin receptors
González N et al. (2015) Bombesin receptor subtype 3 as a potential target for obesity and diabetes. Expert Opin. Ther. Targets 19: 1153‐70 [https://www.ncbi.nlm.nih.gov/pubmed/26066663?dopt=AbstractPlus]
Jensen RT et al. (2008) International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol. Rev. 60: 1‐42 [https://www.ncbi.nlm.nih.gov/pubmed/18055507?dopt=AbstractPlus]
Maina T et al. (2017) Theranostic Prospects of Gastrin‐Releasing Peptide Receptor‐Radioantagonists in Oncology. PET Clin 12: 297‐309 [https://www.ncbi.nlm.nih.gov/pubmed/28576168?dopt=AbstractPlus]
Moreno P et al. (2016) Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment. Expert Opin. Ther. Targets 20: 1055‐73 [https://www.ncbi.nlm.nih.gov/pubmed/26981612?dopt=AbstractPlus]
Qu X et al. (2018) Recent insights into biological functions of mammalian bombesin‐like peptides and their receptors. Curr Opin Endocrinol Diabetes Obes 25: 36‐41 [https://www.ncbi.nlm.nih.gov/pubmed/29120926?dopt=AbstractPlus]
Ramos‐Álvarez I et al. (2015) Insights into bombesin receptors and ligands: Highlighting recent advances. Peptides 72: 128‐44 [https://www.ncbi.nlm.nih.gov/pubmed/25976083?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=10
Overview
Bradykinin (or kinin) receptors (nomenclature as agreed by the NC‐IUPHAR subcommittee on Bradykinin (kinin) Receptors [http://www.ncbi.nlm.nih.gov/pubmed/15734727?dopt=AbstractPlus]) are activated by the endogenous peptides http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=649 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6383, http://www.uniprot.org/uniprot/P01042) (BK), [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=646]http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=646, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6383), Lys‐BK (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=650, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6383)), [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=644]http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=644, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6383), [Phospho‐Ser6]‐Bradykinin, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=639, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6383) (Ile‐SerBK), [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3578]http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3578, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6383) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3580]‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3580, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6383). Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=667 (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema.
Further reading on Bradykinin receptors
Campos MM et al. (2006) Non‐peptide antagonists for kinin B1 receptors: new insights into their therapeutic potential for the management of inflammation and pain. Trends Pharmacol. Sci. 27: 646‐51 [https://www.ncbi.nlm.nih.gov/pubmed/17056130?dopt=AbstractPlus]
Duchene J et al. (2009) The kinin B(1) receptor and inflammation: new therapeutic target for cardiovascular disease. Curr Opin Pharmacol 9: 125‐31 [https://www.ncbi.nlm.nih.gov/pubmed/19124274?dopt=AbstractPlus]
Marceau F et al. (2004) Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov 3: 845‐52 [https://www.ncbi.nlm.nih.gov/pubmed/15459675?dopt=AbstractPlus]
Paquet JL et al. (1999) Pharmacological characterization of the bradykinin B2 receptor: inter‐species variability and dissociation between binding and functional responses. Br. J. Pharmacol. 126: 1083‐90 [https://www.ncbi.nlm.nih.gov/pubmed/10204994?dopt=AbstractPlus]
Thornton E et al. (2010) Kinin receptor antagonists as potential neuroprotective agents in central nervous system injury. Molecules 15: 6598‐618 [https://www.ncbi.nlm.nih.gov/pubmed/20877247?dopt=AbstractPlus]
Whalley ET et al. (2012) Discovery and therapeutic potential of kinin receptor antagonists. Expert Opin Drug Discov 7: 1129‐48 [https://www.ncbi.nlm.nih.gov/pubmed/23095011?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=11
Overview
This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene‐related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [http://www.ncbi.nlm.nih.gov/pubmed/18552275?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12037140?dopt=AbstractPlus]) are generated by the genes https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1440 (which codes for the CT receptor) and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:16709 (which codes for the calcitonin receptor‐like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity‐modifying proteins), which are single TM domain proteins of ca. 130 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CT receptor; these in turn produce variants of the AMY receptor [http://www.ncbi.nlm.nih.gov/pubmed/12037140?dopt=AbstractPlus], some of which can be potently activated by CGRP. The endogenous agonists are the peptides http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=685 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1437, http://www.uniprot.org/uniprot/P01258), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=681‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=681, http://www.uniprot.org/uniprot/P06881) (formerly known as CGRP‐I), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=682 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1438, http://www.uniprot.org/uniprot/P10092) (formerly known as CGRP‐II), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=687 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:5329, http://www.uniprot.org/uniprot/P10997) (occasionally called islet‐amyloid polypeptide, diabetes‐associated polypeptide), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=683 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:259, http://www.uniprot.org/uniprot/P35318) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=684 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:28898, http://www.uniprot.org/uniprot/Q7Z4H4). There are species differences in peptide sequences, particularly for the CTs. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5369 {Pig} (CRSP) is another member of the family with selectivity for the CT receptor but it is not expressed in humans [http://www.ncbi.nlm.nih.gov/pubmed/12556539?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=702 (also known as BIBN4096BS, pKi10.5) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=703 (also known as MK0974, pKi9) are the most selective antagonists available, showing selectivity for CGRP receptors, with a particular preference for those of primate origin. CLR (calcitonin receptor‐like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin.
Comments
It is important to note that a complication with the interpretation of pharmacological studies with AMY receptors in transfected cells is that most of this work has likely used a mixed population of receptors, encompassing RAMP‐coupled CTR as well as CTR alone. This means that although in binding assays human http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=685 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1437, http://www.uniprot.org/uniprot/P01258) has low affinity for 125I‐AMY binding sites, cells transfected with CTR and RAMPs can display potent CT functional responses. Transfection of human CTR with any RAMP can generate receptors with a high affinity for both salmon CT and AMY and varying affinity for different antagonists [http://www.ncbi.nlm.nih.gov/pubmed/10385705?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15692146?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16959943?dopt=AbstractPlus]. The major human CTR splice variant (hCT(a), which does not contain an insert) with RAMP1 (i.e. the AMY1(a) receptor) has a high affinity for CGRP [http://www.ncbi.nlm.nih.gov/pubmed/26125036?dopt=AbstractPlus], unlike hCT(a)‐RAMP3 (i.e. AMY3(a) receptor) [http://www.ncbi.nlm.nih.gov/pubmed/10385705?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15692146?dopt=AbstractPlus]. However, the AMY receptor phenotype is RAMP‐type, splice variant and cell‐line‐dependent [http://www.ncbi.nlm.nih.gov/pubmed/18599553?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22946511?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10871296?dopt=AbstractPlus]. Emerging data suggests that AMY1 could be a second CGRP receptor [http://www.ncbi.nlm.nih.gov/pubmed/29797087?dopt=AbstractPlus].
The ligands described have limited selectivity. Adrenomedullin has appreciable affinity for CGRP receptors. CGRP can show significant cross‐reactivity at AMY receptors and AM2 receptors. Adrenomedullin 2/intermedin also has high affinity for the AM2 receptor [http://www.ncbi.nlm.nih.gov/pubmed/21658025?dopt=AbstractPlus]. CGRP‐(8‐37) acts as an antagonist of CGRP (pKi 8) and inhibits some AM and AMY responses (pKi 6‐7). It is weak at CT receptors. HumanAM‐(22‐52)has some selectivity towardsAM receptors, but with modest potency (pKi 7), limiting its use [http://www.ncbi.nlm.nih.gov/pubmed/12970090?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=702 shows the greatest selectivity between receptors but still has significant affinity for AMY1 receptors [http://www.ncbi.nlm.nih.gov/pubmed/26125036?dopt=AbstractPlus].
Gs is a prominent route for effector coupling for CLR and CTR but other pathways (e.g. Ca2+, ERK, Akt), and G proteins can be activated [http://www.ncbi.nlm.nih.gov/pubmed/20633935?dopt=AbstractPlus]. There is evidence that CGRP‐RCP (a 148 amino‐acid hydrophilic protein, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:746 (http://www.uniprot.org/uniprot/P04424) is important for the coupling of CLR to adenylyl cyclase [http://www.ncbi.nlm.nih.gov/pubmed/10903324?dopt=AbstractPlus].
[125I]‐Salmon CT is the most common radioligand for CT receptors but it has high affinity for AMY receptors and is also poorly reversible.
Further reading on Calcitonin receptors
Hay DL et al. (2018) Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br. J. Pharmacol. 175: 3‐17 [https://www.ncbi.nlm.nih.gov/pubmed/29059473?dopt=AbstractPlus]
Russell FA et al. (2014) Calcitonin gene‐related peptide: physiology and pathophysiology. Physiol. Rev. 94: 1099‐142 [https://www.ncbi.nlm.nih.gov/pubmed/25287861?dopt=AbstractPlus]
Hay DL et al. (2016) Receptor Activity‐Modifying Proteins (RAMPs): New Insights and Roles. Annu. Rev. Pharmacol. Toxicol. 56: 469‐87 [https://www.ncbi.nlm.nih.gov/pubmed/26514202?dopt=AbstractPlus]
Russo AF. (2015) Calcitonin gene‐related peptide (CGRP): a new target for migraine. Annu. Rev. Pharmacol. Toxicol. 55: 533‐52 [https://www.ncbi.nlm.nih.gov/pubmed/25340934?dopt=AbstractPlus]
Kato J et al. (2015) Bench‐to‐bedside pharmacology of adrenomedullin. Eur. J. Pharmacol. 764: 140‐8 [https://www.ncbi.nlm.nih.gov/pubmed/26144371?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=12
Overview
The calcium‐sensing receptor (CaS, provisional nomenclature as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L‐amino acids (particularly L‐Trp and L‐Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/24111791?dopt=AbstractPlus]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [http://www.ncbi.nlm.nih.gov/pubmed/8255296?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9357776?dopt=AbstractPlus], L‐amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [http://www.ncbi.nlm.nih.gov/pubmed/10781086?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10781086?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7493018?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15201280?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9677383?dopt=AbstractPlus]. Indeed, L‐amino acids have been identified as "co‐agonists", with both concomitant calcium and L‐amino acid binding required for full receptor activation [http://www.ncbi.nlm.nih.gov/pubmed/27434672?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/27746744?dopt=AbstractPlus]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [http://www.ncbi.nlm.nih.gov/pubmed/25556167?dopt=AbstractPlus] or decreased extracellular ionic strength [http://www.ncbi.nlm.nih.gov/pubmed/9677383?dopt=AbstractPlus]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.
Comments
The CaS receptor has a number of physiological functions, but it is best known for its central role in parathyroid and renal regulation of extracellular calcium homeostasis [http://www.ncbi.nlm.nih.gov/pubmed/27647839?dopt=AbstractPlus]. This is seen most clearly in patients with loss‐of‐function CaS receptor mutations who develop familial hypocalciuric hypercalcaemia (heterozygous mutations) or neonatal severe hyperparathyroidism (heterozygous, compound heterozygous or homozygous mutations) [http://www.ncbi.nlm.nih.gov/pubmed/27647839?dopt=AbstractPlus] and in Casr null mice [http://www.ncbi.nlm.nih.gov/pubmed/18765830?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7493018?dopt=AbstractPlus], which exhibit similar increases in PTH secretion and blood calcium levels. Gain‐of‐function CaS mutations are associated with autosomal dominant hypocalcaemia and Bartter syndrome type V [http://www.ncbi.nlm.nih.gov/pubmed/27647839?dopt=AbstractPlus].
The CaS receptor primarily couples to Gq/11, G12/13 and Gi/o [http://www.ncbi.nlm.nih.gov/pubmed/22210744?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16247029?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12954603?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22192592?dopt=AbstractPlus], but in some cell types can couple to Gs [http://www.ncbi.nlm.nih.gov/pubmed/20032198?dopt=AbstractPlus]. However, the CaS receptor can form heteromers with Class C GABAB [http://www.ncbi.nlm.nih.gov/pubmed/17591780?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17615148?dopt=AbstractPlus] and mGlu1/5 receptors [http://www.ncbi.nlm.nih.gov/pubmed/11489900?dopt=AbstractPlus], which may introduce further complexity in its signalling capabilities.
Multiple other small molecule chemotypes are positive and negative allosteric modulators of the CaS receptor [http://www.ncbi.nlm.nih.gov/pubmed/21406038?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24050279?dopt=AbstractPlus]. Further, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8375 is a novel peptide positive allosteric modulator of the receptor [http://www.ncbi.nlm.nih.gov/pubmed/23674604?dopt=AbstractPlus]. Agonists and positive allosteric modulators of the CaS receptor are termed Type I and II calcimimetics, respectively, and can suppress parathyroid hormone (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1785 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9606, http://www.uniprot.org/uniprot/P01270)) secretion [http://www.ncbi.nlm.nih.gov/pubmed/9520489?dopt=AbstractPlus]. Negative allosteric modulators are called calcilytics and can act to increase http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1785, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9606) secretion [http://www.ncbi.nlm.nih.gov/pubmed/11561095?dopt=AbstractPlus].
Where functional pKB values are provided for allosteric modulators, this refers to ligand affinity determined in an assay that measures a functional readout of receptor activity (i.e. a receptor signalling assay), as opposed to affinity determined in a radioligand binding assay. The functional pKB may differ depending on the signalling pathway studied. Consult the http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=54&familyId=12&familyType=GPCR#Allosterics for the assay description, as well as other functional readouts.
Further reading on Calcium‐sensing receptor
Brown EM. (2013) Role of the calcium‐sensing receptor in extracellular calcium homeostasis. Best Pract. Res. Clin. Endocrinol. Metab. 27: 333‐43 [https://www.ncbi.nlm.nih.gov/pubmed/23856263?dopt=AbstractPlus]
Hannan FM et al. (2018) The calcium‐sensing receptor in physiology and in calcitropic and noncal citropic diseases. Nat Rev Endocrinol 15: 33‐51 [https://www.ncbi.nlm.nih.gov/pubmed/30443043?dopt=AbstractPlus]
Conigrave AD et al. (2013) Calcium‐sensing receptor (CaSR): pharmacological properties and signaling pathways. Best Pract. Res. Clin. Endocrinol. Metab. 27: 315‐31 [https://www.ncbi.nlm.nih.gov/pubmed/23856262?dopt=AbstractPlus]
Nemeth EF et al. (2018) Discovery and Development of Calcimimetic and Calcilytic Compounds. Prog Med Chem 57: 1‐86 [https://www.ncbi.nlm.nih.gov/pubmed/29680147?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=13
Overview
Cannabinoid receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Cannabinoid Receptors [http://www.ncbi.nlm.nih.gov/pubmed/21079038?dopt=AbstractPlus]) are activated by endogenous ligands that include N‐arachidonoylethanolamine (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2364), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5444‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5444, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5445 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=729. Potency determinations of endogenous agonists at these receptors are complicated by the possibility of differential susceptibility of endogenous ligands to enzymatic conversion [http://www.ncbi.nlm.nih.gov/pubmed/17876303?dopt=AbstractPlus].
There are currently three licenced cannabinoid medicines each of which contains a compound that can activate CB1 and CB2 receptors [http://www.ncbi.nlm.nih.gov/pubmed/23108552?dopt=AbstractPlus]. Two of these medicines were developed to suppress nausea and vomiting produced by chemotherapy. These are http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9071 (Cesamet®), a synthetic CB1/CB2 receptor agonist, and synthetic http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2424 (Marinol®; dronabinol), which can also be used as an appetite stimulant. The third medicine, Sativex®, contains mainly http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2424 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4150, both extracted from cannabis, and is used to treat multiple sclerosis and cancer pain.
Comments
Both CB1 and CB2 receptors may be labelled with [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=734 (0.5 nM;[http://www.ncbi.nlm.nih.gov/pubmed/8819477?dopt=AbstractPlus]) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=736 (2‐2.4 nM; [http://www.ncbi.nlm.nih.gov/pubmed/7651369?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8622639?dopt=AbstractPlus]). http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2364 is also an agonist at vanilloid receptors (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=78%23show_object_507)and http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=86 [http://www.ncbi.nlm.nih.gov/pubmed/17704824?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10440374?dopt=AbstractPlus]. There is evidence for an allosteric site on the CB1 receptor [http://www.ncbi.nlm.nih.gov/pubmed/16113085?dopt=AbstractPlus]. All of the compounds listed as antagonists behave as inverse agonists in some bioassay systems [http://www.ncbi.nlm.nih.gov/pubmed/21079038?dopt=AbstractPlus]. For some cannabinoid receptor ligands, additional pharmacological targets that include GPR55 and GPR119 have been identified [http://www.ncbi.nlm.nih.gov/pubmed/21079038?dopt=AbstractPlus]. Moreover, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=114 although showing little structural similarity to CB1 and CB2 receptors, respond to endogenous agents that are structurally similar to the endogenous cannabinoid ligands [http://www.ncbi.nlm.nih.gov/pubmed/21079038?dopt=AbstractPlus].
Further reading on Cannabinoid receptors
Howlett AC et al. (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 54: 161‐202 [https://www.ncbi.nlm.nih.gov/pubmed/12037135?dopt=AbstractPlus]
Pertwee RG et al. (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB_1 and CB_2. Pharmacol. Rev. 62: 588‐631 [https://www.ncbi.nlm.nih.gov/pubmed/21079038?dopt=AbstractPlus]
Pertwee RG. (2010) Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr. Med. Chem. 17: 1360‐81 [https://www.ncbi.nlm.nih.gov/pubmed/20166927?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=338
Overview
Nomenclature for the chemerin receptors is presented as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/23686350?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/29279348?dopt=AbstractPlus]). The chemoattractant protein and adipokine, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2945 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9868, http://www.uniprot.org/uniprot/Q99969), has been shown to be the endogenous ligand for both chemerin family receptors. Chemerin1 was the founding family member, and when GPR1 was de‐orphanised it was re‐named Chermerin2 [http://www.ncbi.nlm.nih.gov/pubmed/29279348?dopt=AbstractPlus]. Chemerin1 is also activated by the lipid‐derived, antiinflammatory ligand http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3333 (RvE1), which is formed via the sequential metabolism of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3362 by aspirin‐modified cyclooxygenase and lipoxygenase [http://www.ncbi.nlm.nih.gov/pubmed/15753205?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17339491?dopt=AbstractPlus]. In addition, two GPCRs for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3934 (RvD1) have been identified: FPR2/ALX, the lipoxin A4 receptor, and GPR32, an orphan receptor [http://www.ncbi.nlm.nih.gov/pubmed/20080636?dopt=AbstractPlus].
Comments
CCX832 (structure not disclosed) is a selective antagonist, pKi=9.2 [http://www.ncbi.nlm.nih.gov/pubmed/27742615?dopt=AbstractPlus].
Further reading on Chemerin receptors
Kennedy AJ et al. (2018) International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin1) and GPR1 (Chemerin2) Nomenclature, Pharmacology, and Function. Pharmacol. Rev. 70: 174‐196 [https://www.ncbi.nlm.nih.gov/pubmed/29279348?dopt=AbstractPlus]
Shin WJ et al. (2018) Mechanisms and Functions of Chemerin in Cancer: Potential Roles in Therapeutic Intervention. Front Immunol 9: 2772 [https://www.ncbi.nlm.nih.gov/pubmed/30555465?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=14
Overview
Chemokine receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Chemokine Receptors [http://www.ncbi.nlm.nih.gov/pubmed/24218476?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12037138?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10699158?dopt=AbstractPlus]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non‐hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine receptors can be divided by function into two main groups: G protein‐coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non‐G protein‐coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [http://www.ncbi.nlm.nih.gov/pubmed/24218476?dopt=AbstractPlus].
Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β‐chemokines; n= 28), CXC (also known as α‐chemokines; n= 17) and CX3C (n= 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C chemokines (n= 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high‐affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one receptor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein‐coupled chemokine receptors are named acccording to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [http://www.ncbi.nlm.nih.gov/pubmed/25958743?dopt=AbstractPlus]. There can be substantial cross‐species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non‐chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co‐receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include bothstandard chemokine receptor names [http://www.ncbi.nlm.nih.gov/pubmed/10714678?dopt=AbstractPlus] and aliases.
Comments
Specific chemokine receptors facilitate cell entry by microbes, such as ACKR1 for Plasmodium vivax, and CCR5 and CXCR4 for HIV‐1. Virally encoded chemokine receptors are known (e.g. US28, a homologue of CCR1 from human cytomegalovirus and ORF74, which encodes a homolog of CXCR2 in Herpesvirus saimiri and gamma‐Herpesvirus‐68), but their role in viral life cycles is not established. Viruses can exploit or subvert the chemokine system by producing chemokine antagonists and scavengers. Three chemokine receptor antagonists have now been approved by the FDA: 1) the CCR5 antagonist http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=806 (Pfizer) for treatment of HIV/AIDS in patients with CCR5‐using strains; and 2) the CXCR4 antagonist http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=844 (Sanofi) for hematopoietic stem cell mobilization with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4934 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2438, http://www.uniprot.org/uniprot/P09919) in patients undergoing transplantation in the context of chemotherapy for Hodgkins’ Disease and multiple myeloma; and 3) the CCR4 blocking antibody Poteligeo (mogamulizumab‐kpkc, Kyowa Kirin, Inc.) for mycosis fungoides or Sezary syndrome.
Further reading on Chemokine receptors
Bachelerie F et al. (2015) An atypical addition to the chemokine receptor nomenclature: IUPHAR Review 15. Br. J. Pharmacol. 172: 3945‐9 [https://www.ncbi.nlm.nih.gov/pubmed/25958743?dopt=AbstractPlus]
Murphy PM et al. (2000) International Union of Pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol. Rev. 52: 145‐176 [https://www.ncbi.nlm.nih.gov/pubmed/10699158?dopt=AbstractPlus]
Koelink PJ et al. (2012) Targeting chemokine receptors in chronic inflammatory diseases: an extensive review. Pharmacol. Ther. 133: 1‐18 [https://www.ncbi.nlm.nih.gov/pubmed/21839114?dopt=AbstractPlus]
Scholten DJ et al. (2012) Pharmacological modulation of chemokine receptor function. Br. J. Pharmacol. 165: 1617‐43 [https://www.ncbi.nlm.nih.gov/pubmed/21699506?dopt=AbstractPlus]
Murphy PM. (2002) International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature. Pharmacol. Rev. 54: 227‐9 [https://www.ncbi.nlm.nih.gov/pubmed/12037138?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=15
Overview
Cholecystokinin receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on CCK receptors [http://www.ncbi.nlm.nih.gov/pubmed/10581329?dopt=AbstractPlus) are activated by the endogenous peptides cholecystokinin‐8 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=864 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1569, http://www.uniprot.org/uniprot/P06307)), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=860, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1569), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3552, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1569) and gastrin (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3559 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4164, http://www.uniprot.org/uniprot/P01350)). There are only two distinct subtypes of CCK receptors, CCK1 and CCK2 receptors [http://www.ncbi.nlm.nih.gov/pubmed/1373504?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/1313582?dopt=AbstractPlus], with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK1 receptor requiring the carboxyl‐terminal heptapeptide‐amide that includes a sulfated tyrosine for high affinity and potency, while the CCK2 receptor requires only the carboxyl‐terminal tetrapeptide shared by each CCK and gastrin peptides. These receptors have characteristic and distinct distributions, with both present in both the central nervous system and peripheral tissues.
Comments
While a cancer‐specific CCK receptor has been postulated to exist, which also might be responsive to incompletely processed forms of CCK (Gly‐extended forms), this has never been isolated. An alternatively spliced form of the CCK2 receptor in which intron 4 is retained, adding 69 amino acids to the intracellular loop 3 (ICL3) region, has been described to be present particularly in certain neoplasms where mRNA mis‐splicing has been commonly observed [http://www.ncbi.nlm.nih.gov/pubmed/12429993?dopt=AbstractPlus], but it is not clear that this receptor splice form plays a special role in carcinogenesis. Another alternative splicing event for the CCK2 receptor was reported [http://www.ncbi.nlm.nih.gov/pubmed/8415658?dopt=AbstractPlus], with alternative donor sites in exon 4 resulting in long (452 amino acids) and short (447 amino acids) forms of the receptor differing by five residues in ICL3, however, no clear functional differences have been observed.
Further reading on Cholecystokinin receptors
Ballaz S. (2017) The unappreciated roles of the cholecystokinin receptor CCK(1) in brain functioning. Rev Neurosci 28: 573‐585 [https://www.ncbi.nlm.nih.gov/pubmed/28343167?dopt=AbstractPlus]
Dockray GJ. (2009) Cholecystokinin and gut‐brain signalling. Regul. Pept. 155: 6‐10 [https://www.ncbi.nlm.nih.gov/pubmed/19345244?dopt=AbstractPlus]
Cawston EE et al. (2010) Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor. Br. J. Pharmacol. 159: 1009‐21 [https://www.ncbi.nlm.nih.gov/pubmed/19922535?dopt=AbstractPlus]
Dufresne M et al. (2006) Cholecystokinin and gastrin receptors. Physiol. Rev. 86: 805‐47 [https://www.ncbi.nlm.nih.gov/pubmed/16816139?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=25
Overview
Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC‐IUPHAR subcommittee on the Class Frizzled GPCRs [http://www.ncbi.nlm.nih.gov/pubmed/21079039?dopt=AbstractPlus]), are GPCRs originally identified in Drosophila [http://www.ncbi.nlm.nih.gov/pubmed/1334084?dopt=AbstractPlus], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it mediates effects in the Hedgehog signaling pathway [http://www.ncbi.nlm.nih.gov/pubmed/21079039?dopt=AbstractPlus]. FZDs are activated by WNTs, which are cysteine‐rich lipoglycoproteins withfundamentalfunctions inontogeny and tissue homeostasis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5371 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2514, http://www.uniprot.org/uniprot/P35222) or being β‐catenin‐independent (often referred to as canonical vs. non‐canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6697 (http://www.uniprot.org/uniprot/O75197) and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6698 (http://www.uniprot.org/uniprot/O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β‐catenin and subsequently its translocation to the nucleus. β‐Catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. βCatenin‐independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [http://www.ncbi.nlm.nih.gov/pubmed/24032637?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/28790300?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/30049420?dopt=AbstractPlus], the elevation of intracellular calcium [http://www.ncbi.nlm.nih.gov/pubmed/9389482?dopt=AbstractPlus], activation of cGMP‐specific PDE6 [http://www.ncbi.nlm.nih.gov/pubmed/12471263?dopt=AbstractPlus] and elevation of cAMP as well as RAC‐1, JNK, Rho and Rho kinase signalling [http://www.ncbi.nlm.nih.gov/pubmed/19651774?dopt=AbstractPlus]. Novel resonance energy transfer‐based tools have allowed the study of the GPCR‐like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via heterotrimeric G proteins [http://www.ncbi.nlm.nih.gov/pubmed/30514810?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/30737406?dopt=AbstractPlus]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling. Importantly, FZDs exist in at least two distinct conformational states that regulate the pathway selection [http://www.ncbi.nlm.nih.gov/pubmed/30737406?dopt=AbstractPlus]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [http://www.ncbi.nlm.nih.gov/pubmed/12958365?dopt=AbstractPlus], as well as for β‐catenin‐dependent [http://www.ncbi.nlm.nih.gov/pubmed/17426148?dopt=AbstractPlus] and ‐independent [http://www.ncbi.nlm.nih.gov/pubmed/18953287?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17476309?dopt=AbstractPlus] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled‐related proteins (sFRP), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5372 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18081, http://www.uniprot.org/uniprot/Q9Y5W5) (WIF), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3704 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:13771, http://www.uniprot.org/uniprot/Q9BQB4) or Dickkopf (DKK)), as well as modulatory (co)‐receptors with http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=304#Type XV RTKs: RYK, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=304#Type VIII RTKs: ROR1, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=304#Type VIII RTKs: ROR2 and Kremen, which may also function as independent signalling proteins.
Comments
There is limited knowledge about WNT/FZD specificity and which molecular entities determine the signalling outcome of a specific WNT/FZD pair. Understanding of theFZD and SMO coupling to G proteins is incomplete, but progress have been made [http://www.ncbi.nlm.nih.gov/pubmed/27458145?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24032637?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24873871?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26179037?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16885213?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23292797?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22179044?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/30514810?dopt=AbstractPlus]. There is also a scarcity of information on basic pharmacological characteristics of FZDs, such as binding constants, ligand specificity or concentration‐response relationships [http://www.ncbi.nlm.nih.gov/pubmed/19208479?dopt=AbstractPlus]. Development of pharmacological tools for SMO has been faciliated by successful crystalization of several SMO structures [http://www.ncbi.nlm.nih.gov/pubmed/27437577?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/29804838?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25008467?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23636324?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24525480?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/28513578?dopt=AbstractPlus]. The recently solved FZD4 in apo state has provided first insight into FZD transmembranous organization [http://www.ncbi.nlm.nih.gov/pubmed/30135577?dopt=AbstractPlus].
Ligands associated with FZD signalling
WNTs: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3672 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12774, http://www.uniprot.org/uniprot/P04628), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3673 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12780, http://www.uniprot.org/uniprot/P09544) (also known as Int‐1‐related protein), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3674 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12781, http://www.uniprot.org/uniprot/Q93097) (also known as WNT‐13), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3675 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12782, http://www.uniprot.org/uniprot/P56703), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3549 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:15983, http://www.uniprot.org/uniprot/P56704), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3547 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12783, http://www.uniprot.org/uniprot/P56705), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3548 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12784, http://www.uniprot.org/uniprot/P41221) (pEC50 7.7‐8.9 [http://www.ncbi.nlm.nih.gov/pubmed/30514810?dopt=AbstractPlus]), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3676 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:16265, http://www.uniprot.org/uniprot/Q9H1J7), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3678 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12785, http://www.uniprot.org/uniprot/Q9Y6F9), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3679 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12786, http://www.uniprot.org/uniprot/O00755), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3681 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12787, http://www.uniprot.org/uniprot/P56706), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3682 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12788, http://www.uniprot.org/uniprot/Q9H1J5), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3683 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12789, http://www.uniprot.org/uniprot/Q93098), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3684 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12778, http://www.uniprot.org/uniprot/O14904) (also known as WNT‐14), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3686 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12779, http://www.uniprot.org/uniprot/O14905) (also known as WNT‐15 or WNT14b), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3687(https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:13829, http://www.uniprot.org/uniprot/Q9GZT5), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3688 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12775, http://www.uniprot.org/uniprot/O00744) (also known as WNT‐12), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3689 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12776, http://www.uniprot.org/uniprot/O96014) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3690 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:16267, http://www.uniprot.org/uniprot/Q9UBV4).
Extracellular proteins that interact with FZDs: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1063 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7678, http://www.uniprot.org/uniprot/Q00604), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3700 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:16175, http://www.uniprot.org/uniprot/Q2I0M5), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3691 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10776, http://www.uniprot.org/uniprot/Q8N474), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3692 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10777, http://www.uniprot.org/uniprot/Q96HF1), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3693 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3959,http://www.uniprot.org/uniprot/Q92765), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3694 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10778, http://www.uniprot.org/uniprot/Q6FHJ7), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3695 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10779, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10779).
Extracellular proteins that interact with WNTs or LRPs: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3701 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2891, http://www.uniprot.org/uniprot/O94907), https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18081 (http://www.uniprot.org/uniprot/Q9Y5W5), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3704 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:13771, http://www.uniprot.org/uniprot/Q9BQB4), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3702 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:17550, http://www.uniprot.org/uniprot/Q96MU8) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3703 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18797, http://www.uniprot.org/uniprot/Q8NCW0)
Small exogenous ligands: Foxy‐5 [http://www.ncbi.nlm.nih.gov/pubmed/18927296?dopt=AbstractPlus], Box‐5 [http://www.ncbi.nlm.nih.gov/pubmed/19901340?dopt=AbstractPlus], UM206 [http://www.ncbi.nlm.nih.gov/pubmed/21931076?dopt=AbstractPlus], and XWnt8 (http://www.uniprot.org/uniprot/P28026) also known as mini‐Wnt8.
Ligands associated with SMO signalling: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2718, oxysterols [http://www.ncbi.nlm.nih.gov/pubmed/27437577?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/27705744?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/30340023?dopt=AbstractPlus].
Further reading on Class Frizzled GPCRs
Angers S et al. (2009) Proximal events in Wnt signal transduction. Nat. Rev. Mol. Cell Biol. 10: [https://www.ncbi.nlm.nih.gov/pubmed/22935904?dopt=AbstractPlus]
van Amerongen R. (2012) Alternative Wnt pathways and receptors. Cold Spring Harb Perspect Biol 4: 468‐77 [https://www.ncbi.nlm.nih.gov/pubmed/19536106?dopt=AbstractPlus]
Schulte G.(2015)Frizzleds and WNT/β‐cateninsignaling–The black boxof ligand‐receptor selectivity, 113‐39 [https://www.ncbi.nlm.nih.gov/pubmed/26969975?dopt=AbstractPlus]
Wang Y et al. (2016) Frizzled Receptors in Development and Disease. Curr. Top. Dev. Biol. 117: complex stoichiometry and activation kinetics. Eur. J. Pharmacol. 763: 191‐5 [https://www.ncbi.nlm.nih.gov/pubmed/26003275?dopt=AbstractPlus]
Schulte G et al. (2018) Frizzleds as GPCRs ‐ More Conventional Than We Thought! Trends Pharmacol. Sci. 39: 828‐842 [https://www.ncbi.nlm.nih.gov/pubmed/30049420?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=5
Overview
Complement peptide receptors (nomenclature as agreed by the NC‐IUPHAR subcommittee on Complement peptide receptors [http://www.ncbi.nlm.nih.gov/pubmed/23383423?dopt=AbstractPlus]) are activated by the endogenous 75 amino‐acid anaphylatoxin polypeptides http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3640 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1318, http://www.uniprot.org/uniprot/P01024) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=573 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1331, http://www.uniprot.org/uniprot/P01031), generated upon stimulation of the complement cascade. C3a and C5a exert their functions through binding to their receptors (C3aR and C5aR), causing cell activation and triggering cellular degranulation that contributes to the local inflammation.
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3529 has also been reported to have agonist properties at the C3a receptor [http://www.ncbi.nlm.nih.gov/pubmed/16154494?dopt=AbstractPlus]. The putative chemoattractant receptor termed C5a2 (also known as GPR77, C5L2) binds [125I]C5a with no clear signalling function, but has a putative role opposing inflammatory responses [http://www.ncbi.nlm.nih.gov/pubmed/11773063?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15784721?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15715664?dopt=AbstractPlus]. Binding to this site may be displaced with the rank order http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=574 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1331)> http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=573 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1331, http://www.uniprot.org/uniprot/P01031[http://www.ncbi.nlm.nih.gov/pubmed/11773063?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12899627?dopt=AbstractPlus] while there is controversy over the ability of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3640 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1318, http://www.uniprot.org/uniprot/P01024) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5367 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1318, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1318) to compete [http://www.ncbi.nlm.nih.gov/pubmed/15990859?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12540846?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15833747?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12899627?dopt=AbstractPlus]. C5a2 appears to lack G protein signalling and has been termed a decoy receptor [http://www.ncbi.nlm.nih.gov/pubmed/19100624?dopt=AbstractPlus]. However, C5a2 does recruit arrestin after ligand binding, which might provide a signaling pathway for this receptor [http://www.ncbi.nlm.nih.gov/pubmed/20044484?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19641221?dopt=AbstractPlus], and forms heteromers with C5a1. C5a, but not C5a‐des Arg, induces upregulation of heteromer formation between complement C5a receptors C5a1 and C5a2 [http://www.ncbi.nlm.nih.gov/pubmed/24060963?dopt=AbstractPlus]. There are also reports of pro‐inflammatory activity of C5a2, mediated by HMGB1, but the signaling pathway that underlies this is currently unclear (reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/23239822?dopt=AbstractPlus]). More recently, work in T cells has shown that C5a1 and C5a2 act in opposition to each other and that altering the equilibrium between the two receptors, by differential expression or production of C5a‐des Arg (which favours C5a2), can affect the final cellular response [http://www.ncbi.nlm.nih.gov/pubmed/27313051?dopt=AbstractPlus].
Further reading on Complement peptide receptors
Arbore G et al. (2016) A novel "complement‐metabolism‐inflammasome axis" as a key regulator of immune cell effector function. Eur. J. Immunol. 46: 1563‐73 [https://www.ncbi.nlm.nih.gov/pubmed/27184294?dopt=AbstractPlus]
Coulthard LG et al. (2018) Complement C3a receptor modulates embryonic neural progenitor cell proliferation and cognitive performance. Mol. Immunol. 101: 176‐181 [https://www.ncbi.nlm.nih.gov/pubmed/30449309?dopt=AbstractPlus]
Laumonnier Y et al. (2017) Novel insights into the expression pattern of anaphylatoxin receptors in mice and men. Mol. Immunol. 89: 44‐58 [https://www.ncbi.nlm.nih.gov/pubmed/28600003?dopt=AbstractPlus]
Li R et al. (2013) C5L2: a controversial receptor of complement anaphylatoxin, C5a. FASEB J. 27: 855‐64 [https://www.ncbi.nlm.nih.gov/pubmed/23239822?dopt=AbstractPlus]
Monk PN et al. (2007) Function, structure and therapeutic potential of complement C5a receptors. Br. J. Pharmacol. 152: 429‐48 [https://www.ncbi.nlm.nih.gov/pubmed/17603557?dopt=AbstractPlus]
Reichhardt MP et al. (2018) Intracellular complement activation‐An alarm raising mechanism? Semin. Immunol. 38: 54‐62 [https://www.ncbi.nlm.nih.gov/pubmed/29631809?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=19
Overview
Corticotropin‐releasing factor (CRF, nomenclature as agreed by the NC‐IUPHAR subcommittee on Corticotropin‐releasing Factor Receptors [http://www.ncbi.nlm.nih.gov/pubmed/12615952?dopt=AbstractPlus]) receptors are activated by the endogenous peptides http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=912 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2355, http://www.uniprot.org/uniprot/P06850), a 41 aminoacid peptide, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=919 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12516, http://www.uniprot.org/uniprot/P55089), 40 amino‐acids, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=921 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18414, http://www.uniprot.org/uniprot/Q96RP3), 38 amino‐acids and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=928 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:17781, http://www.uniprot.org/uniprot/Q969E3), 38 amino‐acids. CRF1 and CRF2 receptors are activated non‐selectively by CRH and UCN. CRF2 receptors are selectively activated by UCN2 and UCN3. Binding to CRF receptors can be conducted using radioligands [125I]Tyr0‐CRF or [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5389‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5389 with K d values of 0.1‐0.4 nM. CRF1 and CRF2 receptors are non‐selectively antagonized by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=923, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3865) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=925. CRF1 receptors are selectively antagonized by small molecules http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3512, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3520, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3489, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3495, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3496. CRF2 receptors are selectively antagonized by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=931 and astressin 2B.
Comments
A CRF binding protein has been identified (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2356, http://www.uniprot.org/uniprot/P24387) to which both http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=912 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2355, http://www.uniprot.org/uniprot/P06850) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=919 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12516, http://www.uniprot.org/uniprot/P55089) bind with high affinities, which has been suggested to bind and inactivate circulating http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=912, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2355) [http://www.ncbi.nlm.nih.gov/pubmed/7595134?dopt=AbstractPlus].
Further reading on Corticotropin‐releasing factor receptors
Deussing JM et al. (2018) The Corticotropin‐Releasing Factor Family: Physiology of the Stress Response. Physiol. Rev. 98: 2225‐2286 [https://www.ncbi.nlm.nih.gov/pubmed/30109816?dopt=AbstractPlus]
Hauger RL et al. (2003) International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin‐releasing factor and their ligands. Pharmacol Rev. 55: 21‐26 [https://www.ncbi.nlm.nih.gov/pubmed/12615952?dopt=AbstractPlus]
Grammatopoulos DK. (2012) Insights into mechanisms of corticotropin‐releasing hormone receptor signal transduction. Br. J. Pharmacol. 166: 85‐97 [https://www.ncbi.nlm.nih.gov/pubmed/21883143?dopt=AbstractPlus]
Liapakis G et al. (2011) Members of CRF family and their receptors: from past to future. Curr. Med. Chem. 18: 2583‐600 [https://www.ncbi.nlm.nih.gov/pubmed/21568890?dopt=AbstractPlus]
Slater PG et al. (2016) Corticotropin‐Releasing Factor Receptors and Their Interacting Proteins: Functional Consequences. Mol. Pharmacol. 90: 627‐632 [https://www.ncbi.nlm.nih.gov/pubmed/27612874?dopt=AbstractPlus]
Zelenay V et al. (2017) Structures of the First Extracellular Domain of CRF Receptors. Curr Mol Pharmacol 10: 318‐324 [https://www.ncbi.nlm.nih.gov/pubmed/28103782?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=20
Overview
Dopamine receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Dopamine Receptors [1906]) are commonly divided into D1‐like (D1 and D5) and D2‐like (D2, D3 and D4) families, where the endogenous agonist is http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=940.
Comments
The selectivity of many of these agents is less than two orders of magnitude. [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3299 exhibits similar high affinity for D2 and D3 receptors (low affinity for D4), but has been used to label D2 receptors in the presence of a D3‐selective antagonist. [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3296 has similar affinity for D2 and D3 receptors, but labels only D3 receptors in the absence of divalent cations. The pharmacological profile of the D5 receptor is similar to, yet distinct from, that of the D1 receptor. The splice variants of the D2 receptor are commonly termed D2S and D2L (short and long). The DRD4 gene encoding the D4 receptor is highly polymorphic in humans, with allelic variations of the protein from amino acid 387 to 515.
Further reading on Dopamine receptors
Beaulieu JM et al. (2015) Dopamine receptors ‐ IUPHAR Review 13. Br. J. Pharmacol. 172: 1‐23 [https://www.ncbi.nlm.nih.gov/pubmed/25671228?dopt=AbstractPlus]
Beaulieu JM et al. (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol. Rev. 63: 182‐217 [https://www.ncbi.nlm.nih.gov/pubmed/21303898?dopt=AbstractPlus]
Cumming P. (2011) Absolute abundances and affinity states of dopamine receptors in mammalian brain: A review. Synapse 65: 892‐909 [https://www.ncbi.nlm.nih.gov/pubmed/21308799?dopt=AbstractPlus]
Maggio R et al. (2010) Dopamine D2‐D3 receptor heteromers: pharmacological properties and therapeutic significance. Curr Opin Pharmacol 10: 100‐7 [https://www.ncbi.nlm.nih.gov/pubmed/19896900?dopt=AbstractPlus]
Ptácek R et al. (2011) Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders. Med. Sci. Monit. 17: RA215‐20 [https://www.ncbi.nlm.nih.gov/pubmed/21873960?dopt=AbstractPlus]
Schwartz J‐C et al. (1998) Dopamine Receptors. In The IUPHAR Compendium of Receptor Characterization and Classification Edited by Girdlestone D: IUPHAR Media: 141‐151
Undieh AS. (2010) Pharmacology of signaling induced by dopamine D(1)‐like receptor activation. Pharmacol. Ther. 128: 37‐60 [https://www.ncbi.nlm.nih.gov/pubmed/20547182?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=21
Overview
Endothelin receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Endothelin Receptors [http://www.ncbi.nlm.nih.gov/pubmed/12037137?dopt=AbstractPlus]) are activated by the endogenous 21 amino‐acid peptides endothelins 1‐3 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=989 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3176, http://www.uniprot.org/uniprot/P05305), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=990 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3177, http://www.uniprot.org/uniprot/P20800) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1004 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3178, http://www.uniprot.org/uniprot/P14138)).
Comments
Splice variants of the ETA receptor have been identified in rat pituitary cells; one of these, ETAR‐C13, appeared to show loss of function with comparable plasma membrane expression to wild type receptor [http://www.ncbi.nlm.nih.gov/pubmed/17312275?dopt=AbstractPlus]. Subtypes of the ETB receptor have been proposed, although gene disruption studies in mice suggest that only a single gene product exists [http://www.ncbi.nlm.nih.gov/pubmed/9113361?dopt=AbstractPlus]. Crystal structures of the ETB receptor bound to the antagonist http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3494 and ETB selective analogue http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9651 [http://www.ncbi.nlm.nih.gov/pubmed/28805809?dopt=AbstractPlus] and selective ETB agonists http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1004 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3178, http://www.uniprot.org/uniprot/P14138) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3886 [http://www.ncbi.nlm.nih.gov/pubmed/30413709?dopt=AbstractPlus] have been reported.
Further reading on Endothelin receptors
Clozel M et al. (2013) Endothelin receptor antagonists. Handb Exp Pharmacol 218: 199‐227 https://www.ncbi.nlm.nih.gov/pubmed/24092342?dopt=AbstractPlus
Davenport AP. (2002) International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol. Rev. 54: 219‐26 https://www.ncbi.nlm.nih.gov/pubmed/12037137?dopt=AbstractPlus
Davenport AP et al. (2016) Endothelin. Pharmacol. Rev. 68: 357‐418 https://www.ncbi.nlm.nih.gov/pubmed/26956245?dopt=AbstractPlus
Davenport AP et al. (2018) New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine. Physiol Res 67: S37‐S54 https://www.ncbi.nlm.nih.gov/pubmed/29947527?dopt=AbstractPlus
Maguire JJ et al. (2014) Endothelin@25 ‐ new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12. Br. J. Pharmacol. 171: 5555‐72 https://www.ncbi.nlm.nih.gov/pubmed/25131455?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=22
Overview
The G protein‐coupled estrogen receptor (GPER, nomenclature as agreed by the NC‐IUPHAR Subcommittee on the G protein‐coupled estrogen receptor [http://www.ncbi.nlm.nih.gov/pubmed/26023144?dopt=AbstractPlus]) was identified following observations of estrogen‐evoked http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2352 signalling in breast cancer cells [http://www.ncbi.nlm.nih.gov/pubmed/8078914?dopt=AbstractPlus], which mirrored the differential expression of an orphan 7‐transmembrane receptor GPR30 [http://www.ncbi.nlm.nih.gov/pubmed/9367686?dopt=AbstractPlus]. There are observations of both cell‐surface and intracellular expression of the GPER receptor [http://www.ncbi.nlm.nih.gov/pubmed/15705806?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15539556?dopt=AbstractPlus]. Selective agonist/ antagonists for GPER have been characterized [http://www.ncbi.nlm.nih.gov/pubmed/26023144?dopt=AbstractPlus]. Antagonists of the nuclear estrogen receptor, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1015 [http://www.ncbi.nlm.nih.gov/pubmed/11043579?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1016 [http://www.ncbi.nlm.nih.gov/pubmed/15705806?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15539556?dopt=AbstractPlus] and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2820 [http://www.ncbi.nlm.nih.gov/pubmed/24379833?dopt=AbstractPlus], as well as the flavonoid ’phytoestrogens’ http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2826 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5346 [http://www.ncbi.nlm.nih.gov/pubmed/15090535?dopt=AbstractPlus], are agonists of GPER. A complete review of GPER pharmacology has been recently published [http://www.ncbi.nlm.nih.gov/pubmed/26023144?dopt=AbstractPlus]. The roles of GPER in physiological systems throughout the body (cardiovascular, metabolic, endocrine, immune, reproductive) and in cancer have also been reviewed [http://www.ncbi.nlm.nih.gov/pubmed/28595943?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/28249728?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/28343901?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26023144?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26189910?dopt=AbstractPlus].
Comments
Antagonists at the nuclear estrogen receptor, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1015, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1016 [http://www.ncbi.nlm.nih.gov/pubmed/11043579?dopt=AbstractPlus] and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2820 [http://www.ncbi.nlm.nih.gov/pubmed/24379833?dopt=AbstractPlus], as well as the flavonoid ‘phytoestrogens’ http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2826 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5346 [http://www.ncbi.nlm.nih.gov/pubmed/15090535?dopt=AbstractPlus], are agonists at GPER receptors. A complete review of GPER pharmacology has been recently published [http://www.ncbi.nlm.nih.gov/pubmed/26023144?dopt=AbstractPlus].
Further reading on G protein‐coupled estrogen receptor
Barton M et al. (2018) Twenty years of the G protein‐coupled estrogen receptor GPER: Historical and personal perspectives. J. Steroid Biochem. Mol. Biol. 176: 4‐15 https://www.ncbi.nlm.nih.gov/pubmed/28347854?dopt=AbstractPlus
Gaudet HM et al. (2015) The G‐protein coupled estrogen receptor, GPER: The inside and inside‐out story. Mol. Cell. Endocrinol. 418 Pt 3: 207‐19 https://www.ncbi.nlm.nih.gov/pubmed/26190834?dopt=AbstractPlus
Prossnitz ER et al. (2015) International Union of Basic and Clinical Pharmacology. XCVII. G Protein‐Coupled Estrogen Receptor and Its Pharmacologic Modulators. Pharmacol. Rev. 67: 505‐40 https://www.ncbi.nlm.nih.gov/pubmed/26023144?dopt=AbstractPlus
Prossnitz ER et al. (2015) What have we learned about GPER function in physiology and disease from knockout mice? J. Steroid Biochem. Mol. Biol. 153: 114‐26 https://www.ncbi.nlm.nih.gov/pubmed/26189910?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=23
Overview
The http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00510000502765 (nomenclature agreed by the NC‐IUPHAR Subcommittee on the formylpeptide receptor family [http://www.ncbi.nlm.nih.gov/pubmed/19498085?dopt=AbstractPlus]) respond to exogenous ligands such as the bacterial product http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1022 (fMLP) and endogenous ligands such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1031 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:533, http://www.uniprot.org/uniprot/P04083), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3570 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2532, http://www.uniprot.org/uniprot/P08311), amyloid β42, serum amyloid A and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1026, derived from http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5370 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4827, http://www.uniprot.org/uniprot/P68871).
Comments
Note that the data for FPR2/ALX are also reproduced on the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=35 receptor page.
Further reading on Formylpeptide receptors
Dorward DA et al. (2015) The Role of Formylated Peptides and Formyl Peptide Receptor 1 in Governing Neutrophil Function during Acute Inflammation. Am. J. Pathol. 185: 1172‐1184 https://www.ncbi.nlm.nih.gov/pubmed/25791526?dopt=AbstractPlus
Dufton N et al. (2010) Therapeutic anti‐inflammatory potential of formyl‐peptide receptor agonists. Pharmacol. Ther. 127: 175‐88 https://www.ncbi.nlm.nih.gov/pubmed/20546777?dopt=AbstractPlus
Liu M et al. (2012) G protein‐coupled receptor FPR1 as a pharmacologic target in inflammation and human glioblastoma. Int. Immunopharmacol. 14: 283‐8 https://www.ncbi.nlm.nih.gov/pubmed/22863814?dopt=AbstractPlus
Rabiet MJ et al. (2011) N‐formyl peptide receptor 3 (FPR3) departs from the homologous FPR2/ALX receptor with regard to the major processes governing chemoattractant receptor regulation, expression at the cell surface, and phosphorylation. J. Biol. Chem. 286: 26718‐31 https://www.ncbi.nlm.nih.gov/pubmed/21543323?dopt=AbstractPlus
Yazid S et al. (2012) Anti‐inflammatory drugs, eicosanoids and the annexin A1/FPR2 anti‐inflammatory system. Prostaglandins Other Lipid Mediat. 98: 94‐100 https://www.ncbi.nlm.nih.gov/pubmed/22123264?dopt=AbstractPlus
Ye RD et al. (2009) International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol. Rev. 61: 119‐61 https://www.ncbi.nlm.nih.gov/pubmed/19498085?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=24
Overview
Free fatty acid receptors (FFA, nomenclature as agreed by the NC‐IUPHAR Subcommittee on free fatty acid receptors [http://www.ncbi.nlm.nih.gov/pubmed/23686350?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19047536?dopt=AbstractPlus]) are activated by free fatty acids. Long‐chain saturated and unsaturated fatty acids (including C14.0 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2806), C16:0 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1055), C18:1 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1054), C18:2 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1052), C18:3, (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1049), C20:4 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391), C20:5,n‐3 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3362) and C22:6,n‐3 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1051)) activate FFA1 [http://www.ncbi.nlm.nih.gov/pubmed/12496284?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12629551?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12565875?dopt=AbstractPlus] and FFA4 receptors [http://www.ncbi.nlm.nih.gov/pubmed/15619630?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22343897?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20813258?dopt=AbstractPlus], while short chain fatty acids (C2 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1058), C3 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1062), C4 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1059) and C5 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1061)) activate FFA2 [http://www.ncbi.nlm.nih.gov/pubmed/12496283?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12711604?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12684041?dopt=AbstractPlus] and FFA3 [http://www.ncbi.nlm.nih.gov/pubmed/12496283?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12711604?dopt=AbstractPlus] receptors. The crystal structure for agonist bound FFA1 has been described [http://www.ncbi.nlm.nih.gov/pubmed/25043059?dopt=AbstractPlus].
Comments
Short (361 amino acids) and long (377 amino acids) splice variants of human FFA4 have been reported [http://www.ncbi.nlm.nih.gov/pubmed/19723586?dopt=AbstractPlus], which differ by a 16 amino acid insertion in intracellular loop 3, and exhibit differences in intracellular signalling properties in recombinant systems [http://www.ncbi.nlm.nih.gov/pubmed/22282525?dopt=AbstractPlus]. The long FFA4 splice variant has not been identified in other primates or rodents to date [http://www.ncbi.nlm.nih.gov/pubmed/15619630?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19723586?dopt=AbstractPlus].
https://www.genenames.org/data/gene‐symbol‐report/%23!/hgnc_id/HGNC:4500 was originally described as a pseudogene within the family (http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00250000002583), but the discovery of several polymorphisms suggests that some versions of GPR42 may be functional [http://www.ncbi.nlm.nih.gov/pubmed/19630535?dopt=AbstractPlus]. https://www.genenames.org/data/gene‐symbol‐report/%23!/hgnc_id/HGNC:4535 is a structurally‐unrelated G protein‐coupled receptor which has been found to respond to medium chain fatty acids [http://www.ncbi.nlm.nih.gov/pubmed/16966319?dopt=AbstractPlus].
Further reading on Free fatty acid receptors
Bolognini D et al. (2016) The Pharmacology and Function of Receptors for Short‐Chain Fatty Acids. Mol. Pharmacol. 89: 388‐98 https://www.ncbi.nlm.nih.gov/pubmed/26719580?dopt=AbstractPlus
Mancini AD et al. (2013) The fatty acid receptor FFA1/GPR40 a decade later: how much do we know? Trends Endocrinol. Metab. 24: 398‐407 https://www.ncbi.nlm.nih.gov/pubmed/23631851?dopt=AbstractPlus
Milligan G et al. (2017) Complex Pharmacology of Free Fatty Acid Receptors. Chem. Rev. 117: 67‐110 https://www.ncbi.nlm.nih.gov/pubmed/27299848?dopt=AbstractPlus
Moniri NH. (2016) Free‐fatty acid receptor‐4 (GPR120): Cellular and molecular function and its role in metabolic disorders. Biochem. Pharmacol. 110‐111: 1‐15 https://www.ncbi.nlm.nih.gov/pubmed/26827942?dopt=AbstractPlus
Stoddart LA et al. (2008) International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, ‐2, and ‐3: pharmacology and pathophysiological functions. Pharmacol. Rev. 60: 405‐17 [https://www.ncbi.nlm.nih.gov/pubmed/19047536?dopt=AbstractPlus]
Watterson KR et al. (2014) Treatment of type 2 diabetes by free Fatty Acid receptor agonists. Front Endocrinol (Lausanne) 5: 137 [https://www.ncbi.nlm.nih.gov/pubmed/25221541?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=26
Overview
Functional GABAB receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on GABAB receptors [http://www.ncbi.nlm.nih.gov/pubmed/12037141?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17329545?dopt=AbstractPlus]) are formed from the heterodimerization of two similar 7TM subunits termed GABAB1 and GABAB2 [http://www.ncbi.nlm.nih.gov/pubmed/12037141?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17499108?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15451400?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17329545?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17433877?dopt=AbstractPlus]. GABAB receptors are widespread in the CNS and regulate both pre‐ and postsynaptic activity. The GABAB1 subunit, when expressed alone, binds both antagonists and agonists, but the affinity of the latter is generally 10‐100fold less than for the native receptor. Co‐expression of GABAB1 and GABAB2 subunits allows transport of GABAB1 to the cell surface and generates a functional receptor that can couple to signal transduction pathways such as high‐voltage‐activated Ca2+ channels (Cav2.1, Cav2.2), or inwardly rectifying potassium channels (Kir3) [http://www.ncbi.nlm.nih.gov/pubmed/15269338?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12037141?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10604925?dopt=AbstractPlus]. The GABAB1 subunit harbours the GABA (orthosteric)‐binding site within an extracellular domain (ECD) venus flytrap module (VTM), whereas the GABAB2 subunit mediates G protein‐coupled signalling [http://www.ncbi.nlm.nih.gov/pubmed/12037141?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24305054?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22660477?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15451400?dopt=AbstractPlus]. The two subunits interact by direct allosteric coupling [http://www.ncbi.nlm.nih.gov/pubmed/21063387?dopt=AbstractPlus], such that GABAB2 increases the affinity of GABAB1 for agonists and reciprocally GABAB1 facilitates the coupling of GABAB2 to G proteins [http://www.ncbi.nlm.nih.gov/pubmed/24305054?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15922585?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15451400?dopt=AbstractPlus]. GABAB1 and GABAB2 subunits assemble in a 1:1 stoichiometry by means of a coiled‐coil interaction between α‐helices within their carboxy‐termini that masks an endoplasmic reticulum retention motif (RXRR) within the GABAB1 subunit but other domains of the proteins also contribute to their heteromerization [http://www.ncbi.nlm.nih.gov/pubmed/15269338?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24778228?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15451400?dopt=AbstractPlus]. Recent evidence indicates that higher order assemblies of GABAB receptor comprising dimers of heterodimers occur in recombinant expression systems and in vivo and that such complexes exhibit negative functional cooperativity between heterodimers [http://www.ncbi.nlm.nih.gov/pubmed/21552208?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19723778?dopt=AbstractPlus]. Adding further complexity, KCTD (potassium channel tetramerization proteins) 8, 12, 12b and 16 associate as tetramers with the carboxy terminus of the GABAB2 subunit to impart altered signalling kinetics and agonist potency to the receptor complex [http://www.ncbi.nlm.nih.gov/pubmed/20406808?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20400944?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24836506?dopt=AbstractPlus] and are reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/20655485?dopt=AbstractPlus]. The molecular complexity of GABAB receptors is further increased through association with trafficking and effector proteins [Schwenk et al., 2016, Nature Neuroscience 19(2): 233‐42] and reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/27905440?dopt=AbstractPlus]. Four isoforms of the human GABAB1 subunit have been cloned. The predominant GABAB1a and GABAB1b isoforms, which are most prevalent in neonatal and adult brain tissue respectively, differ in their ECD sequences as a result of the use of alternative transcription initiation sites. GABAB1a‐containing heterodimers localise todistal axonsand mediate inhibition of glutamate release in the CA3‐CA1 terminals, and GABA release onto the layer 5 pyramidal neurons, whereas GABAB1b‐containing receptors occur within dendritic spines and mediate slow postsynaptic inhibition [http://www.ncbi.nlm.nih.gov/pubmed/16701210?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16701209?dopt=AbstractPlus]. Only the 1a and 1b variants are identified as components of native receptors [http://www.ncbi.nlm.nih.gov/pubmed/12037141?dopt=AbstractPlus]. Additional GABAB1 subunit isoforms have been described in rodents and humans [http://www.ncbi.nlm.nih.gov/pubmed/21124972?dopt=AbstractPlus] and reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/15269338?dopt=AbstractPlus].
Subunits
Comments
Potencies of agonists and antagonists listed in the table, quantified as IC50 values for the inhibition of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5381 binding to rat cerebral cortex membranes, are from [http://www.ncbi.nlm.nih.gov/pubmed/12037141?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21428811?dopt=AbstractPlus, 635]. Radioligand K D values relate to binding to rat brain membranes. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1074 is a photoaffinity ligand for the GABAB1 subunit [http://www.ncbi.nlm.nih.gov/pubmed/10658574?dopt=AbstractPlus]. CGP27492 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1081), CGP35024 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1080) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1082 act as antagonists at human GABAA ρ1 receptors, with potencies in the low micromolar range [http://www.ncbi.nlm.nih.gov/pubmed/21428811?dopt=AbstractPlus]. In addition to the ligands listed in the table, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=707 binds to the VTM of the GABAB1 subunit to act as a positive allosteric modulator of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1067 [http://www.ncbi.nlm.nih.gov/pubmed/10692480?dopt=AbstractPlus]. Synthetic positive allosteric modulators with low, or no, intrinsic activity include http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1079, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5446, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5503 [http://www.ncbi.nlm.nih.gov/pubmed/21181127?dopt=AbstractPlus] and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5504 [http://www.ncbi.nlm.nih.gov/pubmed/17894647?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15269338?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15126507?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21428811?dopt=AbstractPlus]. The site of action of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1079 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5446 appears to be on the heptahelical domain of the GABAB2 subunit [http://www.ncbi.nlm.nih.gov/pubmed/16966477?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15451400?dopt=AbstractPlus]. In the presence of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1079 or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5446, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1069 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1068 behave as partial agonists [http://www.ncbi.nlm.nih.gov/pubmed/21428811?dopt=AbstractPlus]. A negative allosteric modulator of GABAB activity has been reported [http://www.ncbi.nlm.nih.gov/pubmed/25050158?dopt=AbstractPlus]. Knock‐out of the GABAB1 subunit in C57B mice causes the development of severe tonic‐clonic convulsions that prove fatal within a month of birth, whereas GABAB1 ‐/‐ BALB/c mice, although also displaying spontaneous epileptiform activity, are viable. The phenotype of the latter animals additionally includes hyperalgesia, hyperlocomotion (in a novel, but not familiar, environment), hyperdopaminergia, memory impairment and behaviours indicative of anxiety [http://www.ncbi.nlm.nih.gov/pubmed/15451397?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16606363?dopt=AbstractPlus]. A similar phenotype has been found for GABAB2 ‐/‐ BALB/c mice [http://www.ncbi.nlm.nih.gov/pubmed/15240800?dopt=AbstractPlus].
Further reading on GABAB receptors
Bowery NG et al. (2002) International Union of Pharmacology. XXXIII. Mammalian gammaaminobutyricacid(B) receptors: structure and function. Pharmacol Rev. 54: 247‐264 [https://www.ncbi.nlm.nih.gov/pubmed/12037141?dopt=AbstractPlus]
Froestl W. (2011) An historical perspective on GABAergic drugs. Future Med Chem 3: 163‐75 [https://www.ncbi.nlm.nih.gov/pubmed/21428811?dopt=AbstractPlus]
Gassmann M et al. (2012) Regulation of neuronal GABA(B) receptor functions by subunit composition. Nat. Rev. Neurosci. 13: 380‐94 [https://www.ncbi.nlm.nih.gov/pubmed/22595784?dopt=AbstractPlus]
Pin JP et al. (2016) Organization and functions of mGlu and GABAB receptor complexes. Nature 540: 60‐68 [https://www.ncbi.nlm.nih.gov/pubmed/27905440?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=27
Overview
Galanin receptors (provisional nomenclature as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) are activated by the endogenous peptides http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3592 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4114, http://www.uniprot.org/uniprot/P22466) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3594 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:24840, http://www.uniprot.org/uniprot/Q9UBC7). Human http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3592 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4114, http://www.uniprot.org/uniprot/P22466) is a 30 amino‐acid non‐amidated peptide [http://www.ncbi.nlm.nih.gov/pubmed/1714839?dopt=AbstractPlus]; in other species, it is 29 amino acids long and C‐terminally amidated. Amino acids 1–14 of galanin are highly conserved in mammals, birds, reptiles, amphibia and fish. Shorter peptide species (e.g. human galanin‐1–19 [http://www.ncbi.nlm.nih.gov/pubmed/1710578?dopt=AbstractPlus] and porcine galanin‐5–29 [http://www.ncbi.nlm.nih.gov/pubmed/1283627?dopt=AbstractPlus]) and N‐terminally extended forms (e.g. N‐terminally seven and nine residue elongated forms of porcine galanin [http://www.ncbi.nlm.nih.gov/pubmed/1718731?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/1283627?dopt=AbstractPlus]) have been reported.
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5356) is a high‐affinity agonist at GAL1/GAL2 (pKi 9), and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5357) is selective for GAL2 and GAL3 compared with GAL1 [http://www.ncbi.nlm.nih.gov/pubmed/15944007?dopt=AbstractPlus]. [125I]‐[Tyr26]galanin binds to all three subtypes with K d values generally reported to range from 0.05 to 1 nM, depending on the assay conditions used [http://www.ncbi.nlm.nih.gov/pubmed/9808667?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/2436195?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9305929?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9722565?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9281594?dopt=AbstractPlus]. Porcine galanin‐(3‐29) does not bind to cloned GAL1, GAL2 or GAL3 receptors, but a receptor that is functionally activated by porcine galanin‐(3–29) has been reported in pituitary and gastric smooth muscle cells [http://www.ncbi.nlm.nih.gov/pubmed/7529309?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7683428?dopt=AbstractPlus]. Additional galanin receptor subtypes are also suggested from studies with chimeric peptides (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3896, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3898 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3899), which act as antagonists in functional assays in the cardiovascular system [http://www.ncbi.nlm.nih.gov/pubmed/7693918?dopt=AbstractPlus], spinal cord [http://www.ncbi.nlm.nih.gov/pubmed/1373497?dopt=AbstractPlus], locus coeruleus, hippocampus [http://www.ncbi.nlm.nih.gov/pubmed/1720557?dopt=AbstractPlus] and hypothalamus [http://www.ncbi.nlm.nih.gov/pubmed/7504301?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/1283559?dopt=AbstractPlus], but exhibit agonist activity at some peripheral sites [http://www.ncbi.nlm.nih.gov/pubmed/7504301?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7529309?dopt=AbstractPlus]. The chimeric peptides http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3896, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3897, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3898, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3899 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3861 are agonists at GAL1 receptors expressed endogenously in Bowes human melanoma cells [http://www.ncbi.nlm.nih.gov/pubmed/10601261?dopt=AbstractPlus], and at heterologously expressed recombinant GAL1, GAL2 and GAL3 receptors [http://www.ncbi.nlm.nih.gov/pubmed/9808667?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9305929?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9722565?dopt=AbstractPlus]. Recent studies have described the synthesis of a series of novel, systemically‐active, galanin analogues, with modest preferential binding at the GAL2 receptor. Specific chemical modifications to the galanin backbone increased brain levels of these peptides after i.v. injection and several of these peptides exerted a potent antidepressant‐like effect in mouse models of depression [http://www.ncbi.nlm.nih.gov/pubmed/23600864?dopt=AbstractPlus].
Further reading on Galanin receptors
Foord SM et al. (2005) International Union of Pharmacology. XLVI. G protein‐coupled receptor list. Pharmacol Rev 57: 279‐288 [https://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]
Lang R et al. (2015) Physiology, signaling, and pharmacology of galanin peptides and receptors: three decades of emerging diversity. Pharmacol. Rev. 67: 118‐75 [https://www.ncbi.nlm.nih.gov/pubmed/25428932?dopt=AbstractPlus]
Lang R et al. (2011) The galanin peptide family in inflammation. Neuropeptides 45: 1‐8 [https://www.ncbi.nlm.nih.gov/pubmed/21087790?dopt=AbstractPlus]
Lawrence C et al. (2011) Galanin‐like peptide (GALP) is a hypothalamic regulator of energy homeostasis and reproduction. Front Neuroendocrinol 32: 1‐9 [https://www.ncbi.nlm.nih.gov/pubmed/20558195?dopt=AbstractPlus]
Webling KE et al. (2012) Galanin receptors and ligands. Front Endocrinol (Lausanne) 3: 146 [https://www.ncbi.nlm.nih.gov/pubmed/23233848?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=28
Overview
The ghrelin receptor (nomenclature as agreed by the NC‐IUPHAR Subcommittee for the Ghrelin receptor [http://www.ncbi.nlm.nih.gov/pubmed/16382107?dopt=AbstractPlus]) is activated by a 28 amino‐acid peptide originally isolated from rat stomach, where it is cleaved from a 117 aminoacid precursor (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18129, http://www.uniprot.org/uniprot/Q9UBU3). The human gene encoding the precursor peptide has 83% sequence homology to rat preproghrelin, although the mature peptides from rat and human differ by only two amino acids [http://www.ncbi.nlm.nih.gov/pubmed/11549267?dopt=AbstractPlus]. Alternative splicing results in the formation of a second peptide, [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3600 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18129, http://www.uniprot.org/uniprot/Q9UBU3) with equipotent biological activity [http://www.ncbi.nlm.nih.gov/pubmed/10801861?dopt=AbstractPlus]. A unique post‐translational modification (octanoylation of Ser3, catalysed by ghrelin O‐acyltransferase (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:32311, http://www.uniprot.org/uniprot/Q96T53) [http://www.ncbi.nlm.nih.gov/pubmed/18267071?dopt=AbstractPlus] occurs in both peptides, essential for full activity in binding to ghrelin receptors in the hypothalamus and pituitary, and for the release of growth hormone from the pituitary [http://www.ncbi.nlm.nih.gov/pubmed/10604470?dopt=AbstractPlus]. Structure activity studies showed the first five N‐terminal amino acids to be the minimum required for binding [http://www.ncbi.nlm.nih.gov/pubmed/11087562?dopt=AbstractPlus], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1099 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18129, http://www.uniprot.org/uniprot/Q9UBU3) function [http://www.ncbi.nlm.nih.gov/pubmed/18923064?dopt=AbstractPlus]. In cell systems, the ghrelin receptor is constitutively active [http://www.ncbi.nlm.nih.gov/pubmed/15383539?dopt=AbstractPlus], but this is abolished by a naturally occurring mutation (A204E) that results in decreased cell surface receptor expression and is associated with familial short stature [http://www.ncbi.nlm.nih.gov/pubmed/16511605?dopt=AbstractPlus].
Comments
[http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1098 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18129, http://www.uniprot.org/uniprot/Q9UBU3) has been shown to bind (as [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3810) and have effects in the cardiovascular system [http://www.ncbi.nlm.nih.gov/pubmed/12969753?dopt=AbstractPlus], which raises the possible existence of different receptor subtypes in peripheral tissues and the central nervous system. A potent inverse agonist has been identified ([http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1102, pD 2 8.3; [http://www.ncbi.nlm.nih.gov/pubmed/12907757?dopt=AbstractPlus]). http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3535, described as a ghrelin receptor agonist (pKi 7.8 and pD 2 7.5 at human recombinant ghrelin receptors), has been shown to stimulate ghrelin receptor mediated food intake and gastric emptying but not elicit release of growth hormone, or modify ghrelin stimulated growth hormone release, thus pharmacologically discriminating the orexigenic and gastrointestinal actions of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1099 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18129, http://www.uniprot.org/uniprot/Q9UBU3) from the release of growth hormone [http://www.ncbi.nlm.nih.gov/pubmed/18719021?dopt=AbstractPlus]. A number of selective antagonists have been reported, including peptidomimetic [http://www.ncbi.nlm.nih.gov/pubmed/22798076?dopt=AbstractPlus] and non‐peptide small molecules including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5870 [http://www.ncbi.nlm.nih.gov/pubmed/21034740?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20593439?dopt=AbstractPlus].
Further reading on Ghrelin receptor
Andrews ZB. (2011) The extra‐hypothalamic actions of ghrelin on neuronal function. Trends Neurosci. 34: 31‐40 [https://www.ncbi.nlm.nih.gov/pubmed/21035199?dopt=AbstractPlus]
Angelidis G et al. (2010) Current and potential roles of ghrelin in clinical practice. J. Endocrinol. Invest. 33: 823‐38 [https://www.ncbi.nlm.nih.gov/pubmed/21293171?dopt=AbstractPlus]
Briggs DI et al. (2011) Metabolic status regulates ghrelin function on energy homeostasis. Neuroendocrinology 93: 48‐57 [https://www.ncbi.nlm.nih.gov/pubmed/21124019?dopt=AbstractPlus]
Callaghan B et al. (2014) Novel and conventional receptors for ghrelin, desacyl‐ghrelin, and pharmacologically related compounds. Pharmacol. Rev. 66: 984‐1001 [https://www.ncbi.nlm.nih.gov/pubmed/25107984?dopt=AbstractPlus]
Davenport AP et al. (2005) International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol. Rev. 57: 541‐6 [https://www.ncbi.nlm.nih.gov/pubmed/16382107?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=29
Overview
The glucagon family of receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on the Glucagon receptor family [http://www.ncbi.nlm.nih.gov/pubmed/12615957?dopt=AbstractPlus]) are activated by the endogenous peptide (27‐44 aa) hormones http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1136 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4191, http://www.uniprot.org/uniprot/P01275), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5194 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4191, http://www.uniprot.org/uniprot/P01275), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1140 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4191, http://www.uniprot.org/uniprot/P01275), glucose‐dependent insulinotropic polypeptide (also known as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3542 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4270, http://www.uniprot.org/uniprot/P09681)), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2270 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4265, http://www.uniprot.org/uniprot/P01286) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3643 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10607, http://www.uniprot.org/uniprot/P09683). One common precursor (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4191) generates http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1136 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4191, http://www.uniprot.org/uniprot/P01275), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5194 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4191, http://www.uniprot.org/uniprot/P01275) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1140 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4191, http://www.uniprot.org/uniprot/P01275) peptides [http://www.ncbi.nlm.nih.gov/pubmed/11179772?dopt=AbstractPlus]. For a recent review on review the current understanding of the structures of GLP‐1 and GLP‐1R, the molecular basis of their interaction, and the signaling events associated with it, see de Graaf et al., 2016 [http://www.ncbi.nlm.nih.gov/pubmed/27630114?dopt=AbstractPlus].
Comments
The glucagon receptor has been reported to interact with receptor activity modifying proteins (RAMPs), specifically http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=52, in heterologous expression systems [http://www.ncbi.nlm.nih.gov/pubmed/12446722?dopt=AbstractPlus], although the physiological significance of this has yet to be established.
Further reading on Glucagon receptor family
Ahrén B. (2019) Glucagon‐like peptide‐1 receptor agonists for type 2 diabetes: A rational drug development. J Diabetes Investig 10: 196‐201 [https://www.ncbi.nlm.nih.gov/pubmed/30099845?dopt=AbstractPlus]
Andersen A et al. (2018) Glucagon‐like peptide 1 in health and disease. Nat Rev Endocrinol 14: 390‐403 [https://www.ncbi.nlm.nih.gov/pubmed/29728598?dopt=AbstractPlus]
Gentilella R et al. (2019) Glucagon‐like peptide‐1 receptor agonists in type 2 diabetes treatment: are they all the same? Diabetes Metab. Res. Rev. 35: e3070 [https://www.ncbi.nlm.nih.gov/pubmed/30156747?dopt=AbstractPlus]
Graaf Cd et al. (2016) Glucagon‐Like Peptide‐1 and Its Class B G Protein‐Coupled Receptors: A Long March to Therapeutic Successes. Pharmacol. Rev. 68: 954‐1013 [https://www.ncbi.nlm.nih.gov/pubmed/27630114?dopt=AbstractPlus]
Romera I et al. (2019) A Review of Practical Issues on the Use of Glucagon‐Like Peptide‐1 Receptor Agonists for the Management of Type 2 Diabetes. Diabetes Ther 10: 5‐19 [https://www.ncbi.nlm.nih.gov/pubmed/30506340?dopt=AbstractPlus]
Trujillo JM et al. (2014) GLP‐1 receptor agonists for type 2 diabetes mellitus: recent developments and emerging agents. Pharmacotherapy 34: 1174‐86 [https://www.ncbi.nlm.nih.gov/pubmed/25382096?dopt=AbstractPlus]
Zhang Y et al. (2017) Cryo‐EM structure of the activated GLP‐1 receptor in complex with a G protein. Nature 546: 248‐253 [https://www.ncbi.nlm.nih.gov/pubmed/28538729?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=30
Overview
Glycoprotein hormone receptors (provisional nomenclature [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) are activated by a non‐covalent heterodimeric glycoprotein made up of a common α chain
(http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3731 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1885, http://www.uniprot.org/uniprot/P01215) https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1885, http://www.uniprot.org/uniprot/P01215), with a unique β chain that confers the biological specificity to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1157 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1885 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3964, http://www.uniprot.org/uniprot/P01215 http://www.uniprot.org/uniprot/P01225), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1159 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1885 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6584, http://www.uniprot.org/uniprot/P01215 http://www.uniprot.org/uniprot/P01229), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1160 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1885 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1886, http://www.uniprot.org/uniprot/P01215 http://www.uniprot.org/uniprot/P01233) or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3920 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1885 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12372, http://www.uniprot.org/uniprot/P01215 http://www.uniprot.org/uniprot/P01222). There is binding cross‐reactivity across the endogenous agonists for each of the glycoprotein hormone receptors. The deglycosylated hormones appear to exhibit reduced efficacy at these receptors [http://www.ncbi.nlm.nih.gov/pubmed/2542111?dopt=AbstractPlus].
Further reading on Glycoprotein hormone receptors
Jiang X et al. (2012) Structure of follicle‐stimulating hormone in complex with the entire ectodomain of its receptor. Proc. Natl. Acad. Sci. U.S.A. 109: 12491‐6 https://www.ncbi.nlm.nih.gov/pubmed/22802634?dopt=AbstractPlus
Kleinau G et al. TSH receptor mutations and disease. http://www.thyroidmanager.org/chapter/tsh‐receptor‐mutations‐and‐diseases/. Accessed on 2017‐02‐23.
Tao YX et al. (2009) Follicle stimulating hormone receptor mutations and reproductive disorders. Prog Mol Biol Transl Sci 89: 115‐31 https://www.ncbi.nlm.nih.gov/pubmed/20374735?dopt=AbstractPlus
Troppmann B et al. (2013) Structural and functional plasticity of the luteinizing hormone/choriogonadotrophin receptor. Hum. Reprod. Update 19: 583‐602 https://www.ncbi.nlm.nih.gov/pubmed/23686864?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=31
Overview
GnRH1 and GnRH2 receptors (provisonal nomenclature [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus], also called Type I and Type II GnRH receptor, respectively [http://www.ncbi.nlm.nih.gov/pubmed/15082521?dopt=AbstractPlus]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [http://www.ncbi.nlm.nih.gov/pubmed/16140177?dopt=AbstractPlus, http:http://www.ncbi.nlm.nih.gov/pubmed/15082521?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15878963?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1162 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4419, http://www.uniprot.org/uniprot/P01148) (p‐Glu‐His‐Trp‐Ser‐Tyr‐Gly‐LeuArg‐Pro‐Gly‐NH2) is a hypothalamic decapeptide also known as luteinizing hormone‐releasing hormone, gonadoliberin, luliberin, gonadorelin or simply as GnRH. It is a member of a family of similar peptides found in many species [http://www.ncbi.nlm.nih.gov/pubmed/16140177?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15082521?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15878963?dopt=AbstractPlus] including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1164 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4420, http://www.uniprot.org/uniprot/O43555) (pGlu‐His‐Trp‐Ser‐His‐Gly‐Trp‐Tyr‐Pro‐Gly‐NH2 (which is also known as chicken GnRH‐II). Receptors for three forms of GnRH exist in some species but only GnRH I and GnRH II and their cognate receptors have been found in mammals [http://www.ncbi.nlm.nih.gov/pubmed/16140177?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15082521?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15878963?dopt=AbstractPlus]. GnRH1 receptors are expressed by pituitary gonadotrophs, where they mediate the effects of GnRH on gonadotropin hormone synthesis and secretion that underpin central control of mammalian reproduction. GnRH analogues are used in assisted reproduction and to treat steroid hormone‐dependent conditions [http://www.ncbi.nlm.nih.gov/pubmed/12072036?dopt=AbstractPlus]. Notably, agonists cause desensitization of GnRH‐stimulated gonadotropin secretion and the consequent reduction in circulating sex steroids is exploited to treat hormone‐dependent cancers of the breast, ovary and prostate [http://www.ncbi.nlm.nih.gov/pubmed/12072036?dopt=AbstractPlus]. GnRH1 receptors are selectively activated by GnRH I and all lack the COOH‐terminal tails found in other GPCRs. GnRH2 receptors do have COOH‐terminal tails and (where tested) are selective for GnRH II over GnRH I. GnRH2 receptors are expressed by some primates but not by humans [http://www.ncbi.nlm.nih.gov/pubmed/12538601?dopt=AbstractPlus]. Phylogenetic classifications divide GnRH receptors into three [http://www.ncbi.nlm.nih.gov/pubmed/15082521?dopt=AbstractPlus] or five groups [http://www.ncbi.nlm.nih.gov/pubmed/25344287?dopt=AbstractPlus] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene.
Comments
GnRH1 and GnRH2 receptors couple primarily to Gq/11 [http://www.ncbi.nlm.nih.gov/pubmed/10734055?dopt=AbstractPlus] but coupling to Gs and Gi is evident in some systems [http://www.ncbi.nlm.nih.gov/pubmed/12591945?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8013367?dopt=AbstractPlus]. GnRH2 receptors may also mediate (heterotrimeric) G protein‐independent signalling to protein kinases [http://www.ncbi.nlm.nih.gov/pubmed/15059960?dopt=AbstractPlus]. There is increasing evidence for expression of GnRH receptors on hormone‐dependent cancer cells where they can exert antiproliferative and/or proapoptotic effects and mediate effects of cytotoxins conjugated to GnRH analogues [http://www.ncbi.nlm.nih.gov/pubmed/15561800?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15613448?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/14726258?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15350601?dopt=AbstractPlus]. In some human cancer cell models http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1164 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4420, http://www.uniprot.org/uniprot/O43555) is more potent than http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1162 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4419, http://www.uniprot.org/uniprot/P01148), implying mediation by GnRH2 receptors [http://www.ncbi.nlm.nih.gov/pubmed/12237622?dopt=AbstractPlus], but GnRH2 receptors are not expressed by humans because the human GNRHR2 gene contains a frame shift and internal stop codon [http://www.ncbi.nlm.nih.gov/pubmed/12538601?dopt=AbstractPlus]. The possibility remains that this gene generates GnRH2 receptor‐related proteins (other than the full‐length receptor) that mediate responses to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1164 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4420, http://www.uniprot.org/uniprot/O43555) (see [http://www.ncbi.nlm.nih.gov/pubmed/11861490?dopt=AbstractPlus]). Alternatively, evidence for multiple active GnRH receptor conformations [http://www.ncbi.nlm.nih.gov/pubmed/15059960?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22808094?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20009083?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15492280?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15082521?dopt=AbstractPlus] raises the possibility that GnRH1 receptor‐mediated proliferation inhibition in hormone‐dependent cancer cells is dependent upon a conformation that couples to Gi rather than Gq/11 proteins as in pituitary cells [http://www.ncbi.nlm.nih.gov/pubmed/22808094?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15492280?dopt=AbstractPlus]. Loss‐of‐function mutations in the GnRH1 receptor and deficiency of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1162 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4419, http://www.uniprot.org/uniprot/P01148) are associated with hypogonadotropic hypogonadism although some ’loss of function’ mutations may actually prevent trafficking of ’functional’ GnRH1 receptors to the cell surface, as evidenced by recovery of function by nonpeptide antagonists [http://www.ncbi.nlm.nih.gov/pubmed/12843188?dopt=AbstractPlus]. Human GnRH1 receptors are poorly expressed at the cell surface because of failure to meet structural quality control criteria for endoplasmic reticulum exit [http://www.ncbi.nlm.nih.gov/pubmed/19888967?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12843188?dopt=AbstractPlus], and this increases susceptibility to point mutations that further impair trafficking [http://www.ncbi.nlm.nih.gov/pubmed/19888967?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12843188?dopt=AbstractPlus]. GnRH receptor signalling may require receptor oligomerisation [http://www.ncbi.nlm.nih.gov/pubmed/6282571?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11278883?dopt=AbstractPlus].
Further reading on Gonadotrophin‐releasing hormone receptors
Desaulniers AT et al. (2017) Expression and Role of Gonadotropin‐Releasing Hormone 2 and Its Receptor in Mammals. Front Endocrinol (Lausanne) 8: 269 https://www.ncbi.nlm.nih.gov/pubmed/29312140?dopt=AbstractPlus
Limonta P et al. (2012) GnRH receptors in cancer: from cell biology to novel targeted therapeutic strategies. Endocr. Rev. 33: 784‐811 https://www.ncbi.nlm.nih.gov/pubmed/22778172?dopt=AbstractPlus
McArdle CA and Roberson MS.. (2015) Gonadotropes and gonadotropin‐releasing hormone signaling. In Knobil and Neill's Physiology of Reproduction (4th edition). Edited by Plant TM and Zeleznik AJ.: Elsevier Inc.: [ISBN: 9780123971753]
Millar RP et al. (2004) Gonadotropin‐releasing hormone receptors. Endocr Rev 25: 235‐275 https://www.ncbi.nlm.nih.gov/pubmed/15082521?dopt=AbstractPlus
Tao YX et al. (2014) Chaperoning G protein‐coupled receptors: from cell biology to therapeutics. Endocr. Rev. 35: 602‐47 https://www.ncbi.nlm.nih.gov/pubmed/24661201?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=114
Overview
GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB1 and CB2 cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [http://www.ncbi.nlm.nih.gov/pubmed/21079038?dopt=AbstractPlus]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated in vitro by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3635, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4028 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2661, respectively, there is a lack of evidence for activation by these lipid messengers in vivo. As such, therefore, these receptors retain their orphan status.
Comments
GPR18 failed to respond to a variety of lipid‐derived agents in an in vitro screen [http://www.ncbi.nlm.nih.gov/pubmed/19286662?dopt=AbstractPlus], but has been reported to be activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2424 [http://www.ncbi.nlm.nih.gov/pubmed/21595653?dopt=AbstractPlus]. GPR55 responds to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3317 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=743 at micromolar concentrations, compared to their nanomolar affinity as CB1 receptor antagonists/inverse agonists [http://www.ncbi.nlm.nih.gov/pubmed/21079038?dopt=AbstractPlus]. It has been reported that http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4028 acts at other sites in addition to GPR55 [http://www.ncbi.nlm.nih.gov/pubmed/23714700?dopt=AbstractPlus]. N‐Arachidonoylserine has been suggested to act as a low efficacy agonist/antagonist at GPR18 in vitro [http://www.ncbi.nlm.nih.gov/pubmed/20346144?dopt=AbstractPlus]. It has also been suggested http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3623 acts, at least in part, through GPR119 [http://www.ncbi.nlm.nih.gov/pubmed/18724386?dopt=AbstractPlus]. Although http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3318 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3319 produce GPR119‐dependent responses in heterologous expression systems, comparison with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2661‐mediated responses suggests additional mechanisms of action [http://www.ncbi.nlm.nih.gov/pubmed/18724386?dopt=AbstractPlus].
Further reading on GPR18, GPR55 and GPR119
Davenport AP et al. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein‐coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol. Rev. 65: 967‐86 https://www.ncbi.nlm.nih.gov/pubmed/23686350?dopt=AbstractPlus
Hassing HA et al. (2016) Biased signaling of lipids and allosteric actions of synthetic molecules for GPR119. Biochem. Pharmacol. 119: 66‐75 https://www.ncbi.nlm.nih.gov/pubmed/27569424?dopt=AbstractPlus
Irving A et al. (2017) Cannabinoid Receptor‐Related Orphan G Protein‐Coupled Receptors. Adv Pharmacol 80: 223‐247 https://www.ncbi.nlm.nih.gov/pubmed/28826536
Liu B et al. (2015) GPR55: from orphan to metabolic regulator? Pharmacol. Ther. 145: 35‐42 https://www.ncbi.nlm.nih.gov/pubmed/24972076?dopt=AbstractPlus
Pertwee RG et al. (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB_1 and CB_2. Pharmacol. Rev. 62: 588‐631 https://www.ncbi.nlm.nih.gov/pubmed/21079038?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=33
Overview
Histamine receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Histamine Receptors [http://www.ncbi.nlm.nih.gov/pubmed/9311023?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26084539?dopt=AbstractPlus]) are activated by the endogenous ligand http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1204. Marked species differences exist between histamine receptor orthologues [http://www.ncbi.nlm.nih.gov/pubmed/9311023?dopt=AbstractPlus]. The human and rat H3 receptor genes are subject to significant splice variance [http://www.ncbi.nlm.nih.gov/pubmed/16415177?dopt=AbstractPlus]. The potency order of histamine at histamine receptor subtypes is H3 = H4 > H2 > H1 [http://www.ncbi.nlm.nih.gov/pubmed/26084539?dopt=AbstractPlus]. Some agonists at the human H3 receptor display significant ligand bias [http://www.ncbi.nlm.nih.gov/pubmed/27864425?dopt=AbstractPlus]. Antagonists of all 4 histamine receptors have clinical uses: H1 antagonists for allergies (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1222), H2 antagonists for acid‐reflux diseases (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1234), H3 antagonists for narcolepsy (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8924/WAKIX; Registered) and H4 antagonists for atopic dermatitis (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8985; Phase IIa) [http://www.ncbi.nlm.nih.gov/pubmed/26084539?dopt=AbstractPlus] and vestibular neuritis (AUV) (SENS‐111 (Seliforant, previously UR‐63325), entered and completed vestibular neuritis (AUV) Phase IIa efficacy and safety trials, respectively) [http://www.ncbi.nlm.nih.gov/pubmed/27673668?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/30152527?dopt=AbstractPlus].
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4026 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1205 are reduced efficacy agonists. The H4 receptor appears to exhibit broadly similar pharmacology to the H3 receptor for imidazole‐containing ligands, although http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1236 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1239 are less potent, while http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1223 acts as a reduced efficacy agonist at the H4 receptor and an antagonist at the H3 receptor [http://www.ncbi.nlm.nih.gov/pubmed/11179434?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11118334?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11179435?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10973974?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11179436?dopt=AbstractPlus]. Moreover, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1269 is identified as a high affinity, full agonist for the human H4 receptor [http://www.ncbi.nlm.nih.gov/pubmed/15947036?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1247 has been used to label the H4 receptor heterologous expression systems.
Further reading on Histamine receptors
Gbahou F et al. (2012) The histamine autoreceptor is a short isoform of the H_3 receptor. Br. J. Pharmacol. 166: 1860‐71 https://www.ncbi.nlm.nih.gov/pubmed/22356432?dopt=AbstractPlus
Nieto‐Alamilla G et al. (2016) The Histamine H3 Receptor: Structure, Pharmacology, and Function. Mol. Pharmacol. 90: 649‐673 https://www.ncbi.nlm.nih.gov/pubmed/27563055?dopt=AbstractPlus
Panula P et al. (2015) International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors. Pharmacol. Rev. 67: 601‐55 https://www.ncbi.nlm.nih.gov/pubmed/26084539?dopt=AbstractPlus
van Rijn RM et al. (2008) Cloning and characterization of dominant negative splice variants of the human histamine H4 receptor. Biochem. J. 414: 121‐31 [https://www.ncbi.nlm.nih.gov/pubmed/18452403?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=48
Overview
The hydroxycarboxylic acid family of receptors (http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00500000271913, nomenclature as agreed by the NC‐IUPHAR Subcommittee on Hydroxycarboxylic acid receptors [http://www.ncbi.nlm.nih.gov/pubmed/23686350?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21454438?dopt=AbstractPlus]) respond to organic acids, including the endogenous hydroxy carboxylic acids 3‐hydroxy butyric acid and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2932, as well as the lipid lowering agents http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1588 (niacin), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1596 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1595 [http://www.ncbi.nlm.nih.gov/pubmed/12646212?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12563315?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12522134?dopt=AbstractPlus]. These receptors were provisionally described as nicotinic acid receptors, although nicotinic acid shows submicromolar potency at HCA2 receptors only and is unlikely to be the natural ligand [http://www.ncbi.nlm.nih.gov/pubmed/12563315?dopt=AbstractPlus, https://www.ncbi.nlm.nih.gov/pubmed/12522134?dopt=AbstractPlus].
Comments
Further closely‐related GPCRs include the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=35 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:24884, http://www.uniprot.org/uniprot/Q8TDS5)and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4486 (http://www.uniprot.org/uniprot/O00270). Lactate activates HCA1 on adipocytes in an autocrine manner. It inhibits lipolysis and thereby promotes anabolic effects. HCA2 and HCA3 regulate adipocyte lipolysis and immune functions under conditions of increased FFA formation through lipolysis (e.g., during fasting). HCA2 agonists acting mainly through the receptor on immune cells exert antiatherogenic and anti‐inflammatory effects. HCA2 is also a receptor for butyrate and mediates some of the beneficial effects of short‐chain fatty acids produced by gut microbiota. HCA3 has been shown to be activated by aromatic D‐amino acids.
Further reading on Hydroxycarboxylic acid receptors
Boatman PD et al. (2008) Nicotinic acid receptor agonists. J. Med. Chem. 51: 7653‐62 https://www.ncbi.nlm.nih.gov/pubmed/18983141?dopt=AbstractPlus
Graff EC et al. (2016) Anti‐inflammatory effects of the hydroxycarboxylic acid receptor 2. Metab. Clin. Exp. 65: 102‐13 https://www.ncbi.nlm.nih.gov/pubmed/26773933?dopt=AbstractPlus
Kamanna VS et al. (2013) Recent advances in niacin and lipid metabolism. Curr. Opin. Lipidol. 24: 239‐45 [https://www.ncbi.nlm.nih.gov/pubmed/23619367?dopt=AbstractPlus]
Offermanns S. (2017) Hydroxy‐Carboxylic Acid Receptor Actions in Metabolism. Trends Endocrinol. Metab. 28: 227‐236 https://www.ncbi.nlm.nih.gov/pubmed/28087125?dopt=AbstractPlus
Offermanns S et al. (2011) International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy‐carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B). Pharmacol. Rev. 63: 269‐90 https://www.ncbi.nlm.nih.gov/pubmed/21454438?dopt=AbstractPlus
Offermanns S et al. (2015) Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation. Trends Mol Med 21: 245‐55 https://www.ncbi.nlm.nih.gov/pubmed/25766751?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=34
Overview
The kisspeptin receptor (nomenclature as agreed by the NC‐IUPHAR Subcommittee on the kisspeptin receptor [http://www.ncbi.nlm.nih.gov/pubmed/21079036?dopt=AbstractPlus]), like neuropeptide FF (NPFF), prolactin‐releasing peptide (PrP) and QRFP receptors (provisional nomenclature) responds to endogenous peptides with an arginine‐phenylalanine amide (RFamide) motif. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1288 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6341, http://www.uniprot.org/uniprot/Q15726) (KP54, originally named metastin), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1284 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6341, http://www.uniprot.org/uniprot/Q15726) (KP13) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1283 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6341) (KP10) are biologically‐active peptides cleaved from the https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6341 (http://www.uniprot.org/uniprot/Q15726) gene product. Kisspeptins have roles in, for example, cancer metastasis, fertility/puberty regula tion and glucose homeostasis.
Comments
2‐acylamino‐4,6‐diphenylpyridine derivatives have been described and are the first small molecule kisspeptin receptor antagonists reported with potential for treatment of sex‐hormone dependent diseases such as prostate cancer and endometriosis [http://www.ncbi.nlm.nih.gov/pubmed/20580563?dopt=AbstractPlus] .
Further reading on Kisspeptin receptor
Harter CJL et al. (2018) The role of kisspeptin neurons in reproduction and metabolism. J. Endocrinol. 238: R173‐R183 https://www.ncbi.nlm.nih.gov/pubmed/30042117?dopt=AbstractPlus
Kanda S et al. (2013) Structure, synthesis, and phylogeny of kisspeptin and its receptor. Adv. Exp. Med. Biol. 784: 9‐26 https://www.ncbi.nlm.nih.gov/pubmed/23550000?dopt=AbstractPlus
Kirby HR et al. (2010) International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin receptor nomenclature, distribution, and function. Pharmacol. Rev. 62: 565‐78 https://www.ncbi.nlm.nih.gov/pubmed/21079036?dopt=AbstractPlus
Oakley AE et al. (2009) Kisspeptin signaling in the brain. Endocr. Rev. 30: 713‐43 https://www.ncbi.nlm.nih.gov/pubmed/19770291?dopt=AbstractPlus
Pasquier J et al. (2014) Molecular evolution of GPCRs: Kisspeptin/kisspeptin receptors. J. Mol. Endocrinol. 52: T101‐17 https://www.ncbi.nlm.nih.gov/pubmed/24577719?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=35
Overview
The leukotriene receptors (nomenclature as agreed by the NC‐IUPHAR subcommittee on Leukotriene Receptors [http://www.ncbi.nlm.nih.gov/pubmed/21771892?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24588652?dopt=AbstractPlus]) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT1 receptor is the high affinity LTB4 receptor whereas the BLT2 receptor in addition to being a low‐affinity LTB4 receptor also binds several other lipoxygenase‐products, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3404, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2481, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3401, and the thromboxane synthase product http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6159. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non‐myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB4 has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [http://www.ncbi.nlm.nih.gov/pubmed/9890897?dopt=AbstractPlus] and the vanilloid TRPV1 ligand‐gated nonselective cation channel [http://www.ncbi.nlm.nih.gov/pubmed/16207832?dopt=AbstractPlus]. The receptors for the cysteinyl‐leukotrienes (i.e. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3354, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3353 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3352) aretermed CysLT1 and CysLT2 and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT1 and CysLT2 receptors [http://www.ncbi.nlm.nih.gov/pubmed/24588652?dopt=AbstractPlus]. Cysteinyl‐leukotrienes have also been suggested to signal through the P2Y12 receptor [http://www.ncbi.nlm.nih.gov/pubmed/20702811?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16185654?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19822647?dopt=AbstractPlus], GPR17 [http://www.ncbi.nlm.nih.gov/pubmed/16990797?dopt=AbstractPlus] and GPR99 [http://www.ncbi.nlm.nih.gov/pubmed/23504326?dopt=AbstractPlus].
Comments
The FPR2/ALX receptor (nomenclatureas agreed by the NC‐IUPHAR subcommittee on Leukotriene and Lipoxin Receptors [http://www.ncbi.nlm.nih.gov/pubmed/24588652?dopt=AbstractPlus]) is activated by the endogenous lipidderived, anti‐inflammatory ligands lipoxin A4 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1034) and 15‐epiLXA4 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3933, ATL). The FPR2/ALX receptor also interacts with endogenous peptide and protein ligands, such as MHC binding peptide [http://www.ncbi.nlm.nih.gov/pubmed/10748237?dopt=AbstractPlus] as well as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1031 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:533, http://www.uniprot.org/uniprot/P04083) (ANXA1) and its N‐terminal peptides [http://www.ncbi.nlm.nih.gov/pubmed/24108355?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12368905?dopt=AbstractPlus]. In addition, a soluble hydrolytic product of protease action on the urokinase‐type plasminogen activator receptor has been reported to activate the FPR2/ALX receptor [http://www.ncbi.nlm.nih.gov/pubmed/11818541?dopt=AbstractPlus]. Furthermore, FPR2/ALX has been suggested to act as a receptor mediating the proinflammatory actions of the acute‐phase reactant, serum amyloid A [http://www.ncbi.nlm.nih.gov/pubmed/15171815?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9892621?dopt=AbstractPlus]. The agonist activity of the lipid mediators described has been questioned [http://www.ncbi.nlm.nih.gov/pubmed/23643932?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23607720?dopt=AbstractPlus], which may derive from batchto‐batch differences, partial agonism or biased agonism. Results from Cooray et al. (2013) [http://www.ncbi.nlm.nih.gov/pubmed/24108355?dopt=AbstractPlus] have addressed this issue and the role of homodimers and heterodimers in intracellular signaling. A receptor selective for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5216 has been suggested from functional studies [http://www.ncbi.nlm.nih.gov/pubmed/12794159?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8551217?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8757340?dopt=AbstractPlus]. Note that the data for FPR2/ALX are also reproduced on the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=23.
Oxoeicosanoid receptors (OXE, nomenclature agreed by the NC‐IUPHAR subcommittee on Oxoeicosanoid Receptors [http://www.ncbi.nlm.nih.gov/pubmed/15001665?dopt=AbstractPlus]) are activated by endogenous chemotactic eicosanoid ligands oxidised at the C‐5 position, with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3391 the most potent agonist identified for this receptor. Initial characterization of the heterologously expressed OXE receptor suggested that polyunsaturated fatty acids, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1051 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3362, acted as receptor antagonists [http://www.ncbi.nlm.nih.gov/pubmed/12065583?dopt=AbstractPlus].
Further reading on Leukotriene receptors
Brink C et al. (2004) International Union of Pharmacology XLIV. Nomenclature for the Oxoeicosanoid Receptor. Pharmacol. Rev. 56: 149‐157 https://www.ncbi.nlm.nih.gov/pubmed/15001665?dopt=AbstractPlus
Brink C et al. (2003) International Union of Pharmacology XXXVII. Nomenclature for leukotriene and lipoxin receptors. Pharmacol. Rev. 55: 195‐227 https://www.ncbi.nlm.nih.gov/pubmed/12615958?dopt=AbstractPlus
Bäck M et al. (2011) International Union of Basic and Clinical Pharmacology. LXXXIV: leukotriene receptor nomenclature, distribution, and pathophysiological functions. Pharmacol. Rev. 63: 539‐84 https://www.ncbi.nlm.nih.gov/pubmed/21771892?dopt=AbstractPlus
Bäck M et al. (2014) Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7. Br. J. Pharmacol. 171: 3551‐74 https://www.ncbi.nlm.nih.gov/pubmed/24588652?dopt=AbstractPlus
Laidlaw TM et al. (2012) Cysteinyl leukotriene receptors, old and new; implications for asthma. Clin. Exp. Allergy 42: 1313‐20 https://www.ncbi.nlm.nih.gov/pubmed/22925317?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=36
Overview
Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Lysophospholipid (LPA) receptors Lysophospholipid Receptors [http://www.ncbi.nlm.nih.gov/pubmed/23686350?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24602016?dopt=AbstractPlus]) are activated by the endogenous phospholipid http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2906. The first receptor, LPA1, was identified as ventricular zone gene‐1 (vzg‐1) [http://www.ncbi.nlm.nih.gov/pubmed/8922387?dopt=AbstractPlus], leading to deorphanisation of members of the endothelial differentiation gene (edg) family as other LPA receptors along with sphingosine 1phosphate (S1P) receptors. Additional LPA receptor GPCRs were later identified. Gene names have been codified as LPAR1, etc. to reflect the receptor function of proteins. The crystal structure of LPA1 was solved and demonstrates extracellular LPA access to the binding pocket, consistent with proposed delivery via autotaxin [http://www.ncbi.nlm.nih.gov/pubmed/26091040?dopt=AbstractPlus]. These studies have also implicated cross‐talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The identified receptors can account for most, although not all, LPA‐induced phenomena in the literature, indicating that a majority of LPA‐dependent phenomena are receptor‐mediated. Binding affinities of unlabeled, natural LPA and AEApto LPA1 weremeasured using backscattering interferometry (pKd = 9) [http://www.ncbi.nlm.nih.gov/pubmed/30463988?dopt=AbstractPlus]. Binding affinities were 77‐fold lower than than values obtained using radioactivity [http://www.ncbi.nlm.nih.gov/pubmed/19386608?dopt=AbstractPlus]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Independent validation by multiple groups has been reported in the peer‐reviewed literature for all six LPA receptors described in the tables, including further validation using a distinct read‐out via a novel TGFα “shedding” assay [http://www.ncbi.nlm.nih.gov/pubmed/22983457?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2906 has also been described as an agonist for the transient receptor potential (Trp) ion channel TRPV1 [http://www.ncbi.nlm.nih.gov/pubmed/22101604?dopt=AbstractPlus] and TRPA1 [http://www.ncbi.nlm.nih.gov/pubmed/28176353?dopt=AbstractPlus]. LPA was originally proposed to be a ligand for GPCR35, but data show that in fact it is a receptor for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6479 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:19232, http://www.uniprot.org/uniprot/Q6UXB2) [http://www.ncbi.nlm.nih.gov/pubmed/25411203?dopt=AbstractPlus]. All of these proposed non‐GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors.
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2907 [http://www.ncbi.nlm.nih.gov/pubmed/14500756?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2909 [http://www.ncbi.nlm.nih.gov/pubmed/11723223?dopt=AbstractPlus] and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5450 [http://www.ncbi.nlm.nih.gov/pubmed/15125924?dopt=AbstractPlus] have dual antagonist activity at LPA1 and LPA3 receptors. There is growing evidence for in vivo efficacy of these chemical antagonists in several disorders, including fetal hydrocephalus [http://www.ncbi.nlm.nih.gov/pubmed/21900594?dopt=AbstractPlus], fetal hypoxia [http://www.ncbi.nlm.nih.gov/pubmed/21878565?dopt=AbstractPlus], lung fibrosis [http://www.ncbi.nlm.nih.gov/pubmed/25959255?dopt=AbstractPlus], systemic sclerosis [http://www.ncbi.nlm.nih.gov/pubmed/25959255?dopt=AbstractPlus] and atherosclerosis progression [http://www.ncbi.nlm.nih.gov/pubmed/27883026?dopt=AbstractPlus]. The LPA2 selective agonist, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6580, also shows efficacy in an animal model of multiple sclerosis [http://www.ncbi.nlm.nih.gov/pubmed/28578681?dopt=AbstractPlus]. The LPA5 selective antagonist, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10230, is effective in pain models [http://www.ncbi.nlm.nih.gov/pubmed/29208511?dopt=AbstractPlus].
Further reading on Lysophospholipid (LPA) receptors
Chun J et al. (2010) International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol. Rev. 62: 579‐87 https://www.ncbi.nlm.nih.gov/pubmed/21079037?dopt=AbstractPlus
Kihara Y et al. (2014) Lysophospholipid receptor nomenclature review: IUPHAR Review 8. Br. J. Pharmacol. 171: 3575‐94 https://www.ncbi.nlm.nih.gov/pubmed/24602016?dopt=AbstractPlus
Yung YC et al. (2015) Lysophosphatidic Acid signaling in the nervous system. Neuron 85: 669‐82 https://www.ncbi.nlm.nih.gov/pubmed/25695267?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=135
Overview
Sphingosine 1‐phosphate (S1P) receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Lysophospholipid receptors [http://www.ncbi.nlm.nih.gov/pubmed/24602016?dopt=AbstractPlus]) are activated by the endogenous lipid http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=911 (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family, current gene names have been designated as S1P1R through S1P5R [http://www.ncbi.nlm.nih.gov/pubmed/2160972?dopt=AbstractPlus]. S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or “chaperones”): albumin and HDLbound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [http://www.ncbi.nlm.nih.gov/pubmed/26053123?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26268607?dopt=AbstractPlus]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [http://www.ncbi.nlm.nih.gov/pubmed/29079828?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24667638?dopt=AbstractPlus]. A crystal structure of an S1P1‐T4 fusion protein confirmed aspects and binding, specificity, and receptor activation determined previously through biochemical and genetic studies [http://www.ncbi.nlm.nih.gov/pubmed/30343728?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22344443?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2407 (FTY720), the first drug to target any of the lysophospholipid receptors, binds to four of the five S1PRs, and was the first oral therapy for multiple sclerosis [http://www.ncbi.nlm.nih.gov/pubmed/30625282?dopt=AbstractPlus]. The mechanisms of action of fingolimod and other S1PR modulating drugs in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [http://www.ncbi.nlm.nih.gov/pubmed/21520239?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23518370?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/30255127?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25831442?dopt=AbstractPlus].
Comments
The FDA‐approved immunomodulator http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2407 (FTY720) is phosphorylated in vivo [http://www.ncbi.nlm.nih.gov/pubmed/16078855?dopt=AbstractPlus] to generatean agonist with activity at S1P1, S1P3, S1P4 and S1P5 receptors [http://www.ncbi.nlm.nih.gov/pubmed/11967257?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11923495?dopt=AbstractPlus]. Many of the physiological consequences of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2924 administration, as well as those of other currently described S1P1 agonists, may involve functional antagonism via ubiquitination and subsequent degradation of S1P1 [http://www.ncbi.nlm.nih.gov/pubmed/17237497?dopt=AbstractPlus]. Additionally, receptor specificities of the different compounds may depend on the functional assay system utilized and from which species the receptor sequence originated.
Further reading on Lysophospholipid (S1P) receptors
Chew WS et al. (2016) To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling. Pharmacol. Res. 113: 521‐532 https://www.ncbi.nlm.nih.gov/pubmed/27663260?dopt=AbstractPlus
Chun J et al. (2010) International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol. Rev. 62: 579‐87 https://www.ncbi.nlm.nih.gov/pubmed/21079037?dopt=AbstractPlus
Cyster JG et al. (2012) Sphingosine‐1‐phosphate and lymphocyte egress from lymphoid organs. Annu. Rev. Immunol. 30: 69‐94 https://www.ncbi.nlm.nih.gov/pubmed/22149932?dopt=AbstractPlus
Pyne NJ et al. (2017) Sphingosine 1‐Phosphate Receptor 1 Signaling in Mammalian Cells. Molecules 22: https://www.ncbi.nlm.nih.gov/pubmed/28241498?dopt=AbstractPlus
Rosen H et al. (2013) Sphingosine‐1‐phosphate and its receptors: structure, signaling, and influence. Annu. Rev. Biochem. 82: 637‐62 https://www.ncbi.nlm.nih.gov/pubmed/23527695?dopt=AbstractPlus
Yanagida K et al. (2017) Vascular and Immunobiology of the Circulatory Sphingosine 1‐Phosphate Gradient. Annu. Rev. Physiol. 79: 67‐91 https://www.ncbi.nlm.nih.gov/pubmed/27813829?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=37
Overview
Melanin‐concentrating hormone (MCH) receptors (provisional nomenclature as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) are activated by an endogenous nonadecameric cyclic peptide identical in humans and rats (DFDMLRCMLGRVYRPCWQV; mammalian MCH) generated from a precursor (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9109, http://www.uniprot.org/uniprot/P20382), which also produces http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5374 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9109, http://www.uniprot.org/uniprot/P20382) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5375 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9109, http://www.uniprot.org/uniprot/P20382).
Comments
The MCH2 receptor appears to be a non‐functional pseudogene in rodents [http://www.ncbi.nlm.nih.gov/pubmed/12036292?dopt=AbstractPlus].
Further reading on Melanin‐concentrating hormone receptors
Chung S et al. (2011) Recent updates on the melanin‐concentrating hormone (MCH) and its receptor system: lessons from MCH1R antagonists. J. Mol. Neurosci. 43: 115‐21 [https://www.ncbi.nlm.nih.gov/pubmed/20582487?dopt=AbstractPlus]
Eberle AN et al. (2010) Cellular models for the study of the pharmacology and signaling of melaninconcentrating hormone receptors. J. Recept. Signal Transduct. Res. 30: 385‐402 [https://www.ncbi.nlm.nih.gov/pubmed/21083507?dopt=AbstractPlus]
Foord SM et al. (2005) International Union of Pharmacology. XLVI. G protein‐coupled receptor list. Pharmacol Rev 57: 279‐288 [https://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]
Takase K et al. (2014) Meta‐analysis of melanin‐concentrating hormone signaling‐deficient mice on behavioral and metabolic phenotypes. PLoS ONE 9: e99961 [https://www.ncbi.nlm.nih.gov/pubmed/24924345?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=38
Overview
Melanocortin receptors (provisional nomenclature as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) are activated by members of the melanocortin family (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1320 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9201, http://www.uniprot.org/uniprot/P01189), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3606‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3606, http://www.uniprot.org/uniprot/P01189) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1333‐http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1333, http://www.uniprot.org/uniprot/P01189) forms; δ form is not found in mammals) and adrenocorticotrophin (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3633, http://www.uniprot.org/uniprot/P01189)). Endogenous antagonists include http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3609 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:745, http://www.uniprot.org/uniprot/P42127) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1335 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:330, http://www.uniprot.org/uniprot/O00253). ACTH(1‐24) was approved by the US FDA as a diagnostic agent for adrenal function test, whilst NDP‐MSH was approved by EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development.
Comments
Polymorphisms of the MC1 receptor have been linked to variations in skin pigmentation. Defects of the MC2 receptor underlie familial glucocorticoid deficiency. Polymorphisms of the MC4 receptor have been linked to obesity [http://www.ncbi.nlm.nih.gov/pubmed/9392003?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18779842?dopt=AbstractPlus].
Further reading on Melanocortin receptors
Caruso V et al. (2014) Synaptic changes induced by melanocortin signalling. Nat. Rev. Neurosci. 15: 98‐110 [https://www.ncbi.nlm.nih.gov/pubmed/24588018?dopt=AbstractPlus]
Foord SM et al. (2005) International Union of Pharmacology. XLVI. G protein‐coupled receptor list. Pharmacol Rev 57: 279‐288 [https://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]
Renquist BJ et al. (2011) Physiological roles of the melanocortin MC_3 receptor. Eur. J. Pharmacol. 660: 13‐20 [https://www.ncbi.nlm.nih.gov/pubmed/21211527?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=39
Overview
Melatonin receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Melatonin Receptors [http://www.ncbi.nlm.nih.gov/pubmed/20605968?dopt=AbstractPlus]) are activated by the endogenous ligands http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=224 and clinically used drugs like http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1356, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=198 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7393.
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=224, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1343, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=198, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1349, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1351 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1356 [http://www.ncbi.nlm.nih.gov/pubmed/15695169?dopt=AbstractPlus] are nonselective agonists for MT1 and MT2 receptors. (‐)‐AMMTC displays an ˜400‐fold greater agonist potency than (+)‐AMMTC at rat MT1 receptors (see http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3385 for structure) [http://www.ncbi.nlm.nih.gov/pubmed/10433507?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1363 is an MT1/MT2 non‐selective competitive melatonin receptor antagonist with about 15‐25 fold selectivity for the MT2 receptor [http://www.ncbi.nlm.nih.gov/pubmed/9737724?dopt=AbstractPlus]. MT1/MT2 heterodimers present differentpharmacological profiles from MT1 and MT2 receptors [http://www.ncbi.nlm.nih.gov/pubmed/15266022?dopt=AbstractPlus]. The MT3 binding site of hamster brain and peripheral tissues such as kidney and testis, also termed the ML2 receptor, binds selectively http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5396 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5396 [http://www.ncbi.nlm.nih.gov/pubmed/8773460?dopt=AbstractPlus]. Pharmacological investigations of MT3 binding sites have primarily been conducted in hamster tissues. At this site, The endogenous ligand http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5451 [http://www.ncbi.nlm.nih.gov/pubmed/8246675?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9283717?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9283717?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7798906?dopt=AbstractPlus] and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3393 [http://www.ncbi.nlm.nih.gov/pubmed/7798906?dopt=AbstractPlus] appear to function as agonists, while http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=503 [http://www.ncbi.nlm.nih.gov/pubmed/9283717?dopt=AbstractPlus] functions as an antagonist. The MT3 binding site of hamster kidney was also identified as the hamster homologue of human quinone reductase 2 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7856, http://www.uniprot.org/uniprot/P16083 [http://www.ncbi.nlm.nih.gov/pubmed/10913150?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11331072?dopt=AbstractPlus]). The MT3 binding site activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3393 in eye ciliary body is positively coupled to adenylyl cyclase and regulates chloride secretion [http://www.ncbi.nlm.nih.gov/pubmed/25344385?dopt=AbstractPlus]. Xenopus melanophores and chick brain express a distinct receptor (x420, P49219; c346, P49288, initially termed Mel1C) coupled to the Gi/o family of G proteins, for which GPR50 has recently been suggested to be a mammalian counterpart [http://www.ncbi.nlm.nih.gov/pubmed/18400093?dopt=AbstractPlus] although http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=224 does not bind to GPR50 receptors. Several variants of the MTNR1B gene have been associated with increased type 2 diabetes risk [http://www.ncbi.nlm.nih.gov/pubmed/30531911?dopt=AbstractPlus].
Further reading on Melatonin receptors
Cecon E et al. (2018) Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br. J. Pharmacol. 175: 3263‐3280 [https://www.ncbi.nlm.nih.gov/pubmed/28707298?dopt=AbstractPlus]
Dubocovich ML et al. (2010) International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein‐coupled melatonin receptors. Pharmacol. Rev. 62: 343‐80 [https://www.ncbi.nlm.nih.gov/pubmed/20605968?dopt=AbstractPlus]
Jockers R et al. (2016) Update on melatonin receptors: IUPHAR Review 20. Br. J. Pharmacol. 173: 2702‐25 [https://www.ncbi.nlm.nih.gov/pubmed/27314810?dopt=AbstractPlus]
Karamitri A et al. (2019) Melatonin in type 2 diabetes mellitus and obesity. Nat Rev Endocrinol 15: 105‐125 [https://www.ncbi.nlm.nih.gov/pubmed/30531911?dopt=AbstractPlus]
Liu J et al. (2016) MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. Annu. Rev. Pharmacol. Toxicol. 56: 361‐83 [https://www.ncbi.nlm.nih.gov/pubmed/26514204?dopt=AbstractPlus]
Zlotos DP et al. (2014) MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential. J. Med. Chem. 57: 3161‐85 [https://www.ncbi.nlm.nih.gov/pubmed/24228714?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=40
Overview
Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Metabotropic Glutamate Receptors[1899]) area family of G protein‐coupled receptors activated by the neurotransmitter glutamate. The mGlu family is composed of eight members (named mGlu1 to mGlu8) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group‐I (mGlu1 and mGlu5), Group‐II (mGlu2 and mGlu3) and Group‐III (mGlu4, mGlu6, mGlu7 and mGlu8) (see Further reading).
Structurally, mGlu are composed of three juxtaposed domains: a core G protein‐activating seven‐transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine‐rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi‐lobed extracellular domain where glutamate binds. The structures of the VFTD of mGlu1, mGlu2, mGlu3, mGlu5 and mGlu7 have been solved [http://www.ncbi.nlm.nih.gov/pubmed/11069170?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25602126?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17360426?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11867751?dopt=AbstractPlus]. The structure of the 7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organization similar to that of other GPCRs, although the helices appear more compacted [http://www.ncbi.nlm.nih.gov/pubmed/29455526?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25042998?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24603153?dopt=AbstractPlus]. mGlu form constitutive dimers crosslinked by a disulfide bridge. Recent studies revealed the possible formation of heterodimers between either group‐I receptors, or within and between group‐II and ‐III receptors [http://www.ncbi.nlm.nih.gov/pubmed/20826542?dopt=AbstractPlus]. Although well characterized in transfected cells, co‐localization and specific pharmacological properties also suggest the existence of such heterodimers in the brain [http://www.ncbi.nlm.nih.gov/pubmed/28661401?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24381270?dopt=AbstractPlus].
The endogenous ligands of mGlu are http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1369, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1411, N‐acetylaspartylglutamate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1405) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5447. Group‐I mGlu receptors may be activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1367 and (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1366)http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1366 [http://www.ncbi.nlm.nih.gov/pubmed/8532171?dopt=AbstractPlus] and antagonized by (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5448 [http://www.ncbi.nlm.nih.gov/pubmed/15996690?dopt=AbstractPlus]. Group‐II mGlu receptors may be activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3349 [http://www.ncbi.nlm.nih.gov/pubmed/10090786?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1394], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1393 [http://www.ncbi.nlm.nih.gov/pubmed/9144636?dopt=AbstractPlus http://www.ncbi.nlm.nih.gov/pubmed/9473604?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1377 and (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1392,http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1392)http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1392 [http://www.ncbi.nlm.nih.gov/pubmed/9076745?dopt=AbstractPlus, and antagonised by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1400 [http://www.ncbi.nlm.nih.gov/pubmed/9121605?dopt=AbstractPlus] and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3350 [http://www.ncbi.nlm.nih.gov/pubmed/9871538?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8632404?dopt=AbstractPlus]. Group‐III mGlu receptors may be activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1410 and (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1406)http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1406 [http://www.ncbi.nlm.nih.gov/pubmed/10336568?dopt=AbstractPlus]. An example of an antagonist selective for mGlu receptors is http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1378, which blocks mGlu2 and mGlu3 at low nanomolar concentrations, mGlu8 at high nanomolar concentrations, and mGlu4, mGlu5, and mGlu7 in the micromolar range [http://www.ncbi.nlm.nih.gov/pubmed/9680254?dopt=AbstractPlus]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that bind within the TM domain have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as ‘potentiators’ of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist.
Comments
The activity of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1405 as an agonist at mGlu3 receptors was questioned on the basis of contamination with glutamate [http://www.ncbi.nlm.nih.gov/pubmed/19389924?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19285517?dopt=AbstractPlus], but this has been refuted [http://www.ncbi.nlm.nih.gov/pubmed/21740441?dopt=AbstractPlus].
Radioligand binding using a variety of radioligands has been conducted on recombinant receptors (for example, [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1391 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1391 [http://www.ncbi.nlm.nih.gov/pubmed/12695537?dopt=AbstractPlus] and [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5392 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5392 [http://www.ncbi.nlm.nih.gov/pubmed/15976016?dopt=AbstractPlus] at mGlu1 receptors and [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1425 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1425 [http://www.ncbi.nlm.nih.gov/pubmed/11814808?dopt=AbstractPlus] and [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5394 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5394 [http://www.ncbi.nlm.nih.gov/pubmed/12438526?dopt=AbstractPlus] at mGlu5 receptors; [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1399 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1399 and [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1396 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1396 for mGlu2 and mGlu3 receptors [http://www.ncbi.nlm.nih.gov/pubmed/10530814?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10884552?dopt=AbstractPlus]). Although a number of radioligands have been used to examine binding in native tissues, correlation with individual subtypes is limited. Many pharmacological agents have not been fully tested across all known subtypes of mGlu receptors and may have unappreciated biased or neutral activity at other subtypes [http://www.ncbi.nlm.nih.gov/pubmed/29514854?dopt=AbstractPlus]. Potential differences linked to the species (e.g. human versus rat or mouse) of the receptors and the receptor splice variants are generally not known. The influence of receptor expression level on pharmacology and selectivity has not been controlled for in most studies, particularly those involving functional assays of receptor coupling.
(http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3421 is an antagonist at mGlu1, but is an agonist (albeit of reduced efficacy) at mGlu5 receptors. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1377 also exhibits agonist activity at NMDA glutamate receptors [http://www.ncbi.nlm.nih.gov/pubmed/9106476?dopt=AbstractPlus], and is an antagonist at all Group‐III mGluRs with an IC50 of 30μM. A potential novel metabotropic glutamate receptor coupled to phosphoinositide turnover has been observed in rat brain; it is activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5449 (ineffective as an agonist at recombinant Group I metabotropic glutamate receptors), but is resistant to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1378 [http://www.ncbi.nlm.nih.gov/pubmed/9353394?dopt=AbstractPlus]. There are also reports of a distinct metabotropic glutamatereceptor coupled tophospholipase D in ratbrain, which does not readily fit into the current classification [http://www.ncbi.nlm.nih.gov/pubmed/9175608?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8799579?dopt=AbstractPlus]
A related class C receptor composed of two distinct subunits, T1R1 + T1R3 is also activated by glutamate and is responsible for umami taste detection.
All selective antagonists at metabotropic glutamate receptors are competitive.
Further reading on Metabotropic glutamate receptors
Conn PJ et al. (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 37: 205‐237 [https://www.ncbi.nlm.nih.gov/pubmed/9131252?dopt=AbstractPlus]
Ferraguti F et al. (2006) Metabotropic glutamate receptors. Cell Tissue Res. 326: 483‐504 [https://www.ncbi.nlm.nih.gov/pubmed/16847639?dopt=AbstractPlus]
Nicoletti F et al. (2011) Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60: 1017‐41 [https://www.ncbi.nlm.nih.gov/pubmed/21036182?dopt=AbstractPlus]
Niswender CM et al. (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu. Rev. Pharmacol. Toxicol. 50: 295‐322 [https://www.ncbi.nlm.nih.gov/pubmed/20055706?dopt=AbstractPlus]
Pin JP et al. (2016) Organization and functions of mGlu and GABAB receptor complexes. Nature 540: 60‐68 [https://www.ncbi.nlm.nih.gov/pubmed/27905440?dopt=AbstractPlus]
Rondard P et al. (2011) The complexity of their activation mechanism opens new possibilities for the modulation of mGlu and GABAB class C G protein‐coupled receptors. Neuropharmacology 60: 82‐92 [https://www.ncbi.nlm.nih.gov/pubmed/20713070?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=41
Overview
Motilin receptors (provisional nomenclature) are activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1458 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7141, http://www.uniprot.org/uniprot/P12872), a 22 amino‐acid peptide derived from a precursor (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7141, http://www.uniprot.org/uniprot/P12872), which may also generate a http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5376 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7141, http://www.uniprot.org/uniprot/P12872). These receptors promote gastrointestinal motility and are suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibiotics (often called motilides; e.g. erythromycin), although for many of these molecules the evidence is sparse.
Comments
In terms of structure, the motilin receptor has closest homology with the ghrelin receptor. Thus, the human motilin receptor shares 52% overall amino acid identity with the ghrelin receptor and 86% in the transmembrane regions [http://www.ncbi.nlm.nih.gov/pubmed/19696113?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17183187?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15764739?dopt=AbstractPlus]. However, differences between the N‐terminus regions of these receptors means that their cognate peptide ligands do not readily activate each other [http://www.ncbi.nlm.nih.gov/pubmed/14504130?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19374732?dopt=AbstractPlus]. In laboratory rodents, the gene encoding the motilin percursor appears to be absent, while the receptor appears to be a pseudogene [http://www.ncbi.nlm.nih.gov/pubmed/19696113?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21531468?dopt=AbstractPlus]. Functions of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1458 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7141, http://www.uniprot.org/uniprot/P12872) are not usually detected in rodents, although brain and other responses to motilin and the macrolide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1444 have been reported and the mechanism of these actions is obscure [http://www.ncbi.nlm.nih.gov/pubmed/9441746?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10092986?dopt=AbstractPlus]. Notably, in some non‐laboratory rodents (e.g. the North American kangaroo rat (Dipodomys) and mouse (Microdipodops) a functional form of motilin may exist but the motilin receptor is non‐functional [http://www.ncbi.nlm.nih.gov/pubmed/15027861?dopt=AbstractPlus]. Marked differences in ligand affinities for the motilin receptor in dogs and humans may be explained by significant differences in receptor structure [http://www.ncbi.nlm.nih.gov/pubmed/23189978?dopt=AbstractPlus]. Note that for the complex macrolide structures, selectivity of action has often not been rigorously examined and other actions are possible (e.g. P2X inhibition by erythromycin; [http://www.ncbi.nlm.nih.gov/pubmed/10749750?dopt=AbstractPlus]). Small molecule motilin receptor agonists are now described [http://www.ncbi.nlm.nih.gov/pubmed/15027861?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/19374732?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21544957?dopt=AbstractPlus]. The motilin receptor does not appear to have constitutive activity [http://www.ncbi.nlm.nih.gov/pubmed/12907757?dopt=AbstractPlus]. Although not proven, the existence of biased agonism at the receptor has been suggested [http://www.ncbi.nlm.nih.gov/pubmed/16531413?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17074305?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24438586?dopt=AbstractPlus]. A truncated 5‐transmembrane structure has been identified but this is without activity when transfected into a host cell [http://www.ncbi.nlm.nih.gov/pubmed/10381885?dopt=AbstractPlus]. Receptor dimerisation has not been reported.
Further reading on Motilin receptor
De Smet B et al. (2009) Motilin and ghrelin as prokinetic drug targets. Pharmacol. Ther. 123: 207‐23 [https://www.ncbi.nlm.nih.gov/pubmed/19427331?dopt=AbstractPlus]
Marrinan SL etal. (2018) A randomized, double‐blind, placebo‐controlled trial of camicinal in Parkinson's disease. Mov. Disord. 33: 329‐332 [https://www.ncbi.nlm.nih.gov/pubmed/29278279?dopt=AbstractPlus]
Sanger GJ et al. (2016) Ghrelin and motilin receptors as drug targets for gastrointestinal disorders. Nat Rev Gastroenterol Hepatol 13: 38‐48 [https://www.ncbi.nlm.nih.gov/pubmed/26392067?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=42
Overview
Neuromedin U receptors (provisional nomenclature as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) are activated by the endogenous 25 amino acid peptide neuromedin U (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1470 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7859, http://www.uniprot.org/uniprot/P48645), NmU‐25), a peptide originally isolated from pig spinal cord [http://www.ncbi.nlm.nih.gov/pubmed/3839674?dopt=AbstractPlus]. In humans, NmU‐25 appears to be the sole product of a precursor gene (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7859, http://www.uniprot.org/uniprot/P48645) showing a broad tissue distribution, but which is expressed at highest levels in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NmU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NmU. Despite species differences in NmU structure, the C‐terminal region (particularly the C‐terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1468 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:32203, http://www.uniprot.org/uniprot/Q5H8A3)) has also been identified as an endogenous agonist [http://www.ncbi.nlm.nih.gov/pubmed/15635449?dopt=AbstractPlus]. NmS33 is, as its name suggests, a 33 amino‐acid product of a precursor protein derived from a single gene and contains an amidated Cterminal heptapeptide identical to NmU. NmS‐33 appears to activate NMU receptors with equivalent potency to NmU‐25.
Comments
NMU1 and NMU2 couple predominantly to Gq/11 although there is evidence of good coupling to Gi/o [http://www.ncbi.nlm.nih.gov/pubmed/15331768?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10887190?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17652154?dopt=AbstractPlus]. NMU1 and NMU2 can be labelled with [125I]‐NmU and [125I]‐NmS (of various species, e.g. [http://www.ncbi.nlm.nih.gov/pubmed/18358099?dopt=AbstractPlus]), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3858 or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3863 [http://www.ncbi.nlm.nih.gov/pubmed/15331768?dopt=AbstractPlus]. A range of radiolabelled ( 125I‐), fluorescently labelled (e.g. Cy3, Cy5, rhodamine and FAM) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4787 labelled versions of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1470 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7859, http://www.uniprot.org/uniprot/P48645) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1468 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:32203, http://www.uniprot.org/uniprot/Q5H8A3) are now commercially available.
Further reading on Neuromedin U receptors
Brighton PJ et al. (2004) Neuromedin U and its receptors: structure, function, and physiological roles. Pharmacol. Rev. 56: 231‐48 [https://www.ncbi.nlm.nih.gov/pubmed/15169928?dopt=AbstractPlus]
Budhiraja S et al. (2009) Neuromedin U: physiology, pharmacology and therapeutic potential. Fundam Clin Pharmacol 23: 149‐57 [https://www.ncbi.nlm.nih.gov/pubmed/19645813?dopt=AbstractPlus]
Mitchell JD et al. (2009) Emerging pharmacology and physiology of neuromedin U and the structurally related peptide neuromedin S. Br. J. Pharmacol. 158: 87‐103 [https://www.ncbi.nlm.nih.gov/pubmed/19519756?dopt=AbstractPlus]
Novak CM. (2009) Neuromedin S and U. Endocrinology 150: 2985‐7 [https://www.ncbi.nlm.nih.gov/pubmed/19549882?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=43
Overview
The Neuropeptide FF receptor family contains two subtypes, NPFF1 and NPFF2 (provisional nomenclature [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]), which exhibit high affinities for neuropeptide FF (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7901, http://www.uniprot.org/uniprot/O15130) and RFamide related peptides (RFRP: precursor genesymbol https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:13782, http://www.uniprot.org/uniprot/Q9HCQ7). NPFF1 is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus. NPFF2 is present in high density in the superficial layers of the mammalian spinal cord where it is involved in nociception and modulation of opioid functions.
Comments
An orphan receptor https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4523 (http://www.uniprot.org/uniprot/Q9NYM4) shows sequence similarities with NPFF1, NPFF2, PrRP and QRFP receptors. The antagonist http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1486 is selective for NPFF receptors, but does not distinguish between the NPFF1 and NPFF2 subtypes (pKi 7.1 and 7.2, respectively, [http://www.ncbi.nlm.nih.gov/pubmed/16407169?dopt=AbstractPlus]).
Further reading on Neuropeptide FF/neuropeptide AF receptors
Moulédous L et al. (2010) Opioid‐modulating properties of the neuropeptide FF system. Biofactors 36: 423‐9 [https://www.ncbi.nlm.nih.gov/pubmed/20803521?dopt=AbstractPlus]
Vyas N et al. (2006) Structure‐activity relationships of neuropeptide FF and related peptidic and non‐peptidic derivatives. Peptides 27: 990‐6 [https://www.ncbi.nlm.nih.gov/pubmed/16490282?dopt=AbstractPlus]
Yang HY et al. (2008) Modulatory role of neuropeptide FF system in nociception and opiate analgesia. Neuropeptides 42: 1‐18 [https://www.ncbi.nlm.nih.gov/pubmed/17854890?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=44
Overview
The neuropeptide S receptor (NPS, provisional nomenclature [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) responds to the 20 amino‐acid peptide neuropeptide S derived from a precursor (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:33940, http://www.uniprot.org/uniprot/P0C0P6).
Comments
Multiple single‐nucleotide polymorphisms (SNP) and several splice variants have been identified in the human NPS receptor. The most interesting of these is an Asn‐Ile exchange at position 107 (Asn107Ile). The human NPS receptor Asn107Ile displayed similar binding affinity buthigher NPSpotency (by approx. 10‐fold) than human NPS receptor Asn107 [http://www.ncbi.nlm.nih.gov/pubmed/16144971?dopt=AbstractPlus]. Several epidemiological studies reported an association between Asn107Ile receptor variant and susceptibility to panic disorders [http://www.ncbi.nlm.nih.gov/pubmed/20603625?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20705147?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17669576?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20628342?dopt=AbstractPlus]. The SNP Asn107Ile has also been linked to sleep behavior [http://www.ncbi.nlm.nih.gov/pubmed/17903308?dopt=AbstractPlus], inflammatory bowel disease [http://www.ncbi.nlm.nih.gov/pubmed/17854592?dopt=AbstractPlus], schizophrenia [http://www.ncbi.nlm.nih.gov/pubmed/22078257?dopt=AbstractPlus], increased impulsivity and ADHD symptoms [http://www.ncbi.nlm.nih.gov/pubmed/23325374?dopt=AbstractPlus]. Interestingly, a carboxy‐terminal splice variant of human NPS receptor was found to be overexpressed in asthmatic patients [http://www.ncbi.nlm.nih.gov/pubmed/15073379?dopt=AbstractPlus].
Further reading on Neuropeptide S receptor
Grund T et al. (2019) Brain neuropeptide S: via GPCR activation to a powerful neuromodulator of socio‐emotional behaviors. Cell Tissue Res. 375: 123‐132 [https://www.ncbi.nlm.nih.gov/pubmed/30112573?dopt=AbstractPlus]
Guerrini R et al. (2010) Neurobiology, pharmacology, and medicinal chemistry of neuropeptide S and its receptor. Med Res Rev 30: 751‐77 [https://www.ncbi.nlm.nih.gov/pubmed/19824051?dopt=AbstractPlus]
Ruzza C et al. (2017) Neuropeptide S receptor ligands: a patent review (2005‐2016). Expert Opin Ther Pat 27: 347‐362 [https://www.ncbi.nlm.nih.gov/pubmed/27788040?dopt=AbstractPlus]
Xu YL et al. (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic‐like effects. Neuron 43: 487‐497 [https://www.ncbi.nlm.nih.gov/pubmed/15312648?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=45
Overview
The neuropeptide BW receptor 1 (NPBW1, provisional nomenclature [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) is activated by two 23‐amino‐acid peptides, neuropeptide W (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1495 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30509, http://www.uniprot.org/uniprot/Q8N729)) and neuropeptide B (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1501 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30099, http://www.uniprot.org/uniprot/Q8NG41)) [http://www.ncbi.nlm.nih.gov/pubmed/12118011?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12130646?dopt=AbstractPlus]. C‐terminally extended forms of the peptides (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1496 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30509, http://www.uniprot.org/uniprot/Q8N729) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1502 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30099, http://www.uniprot.org/uniprot/Q8NG41)) also activate NPBW1[http://www.ncbi.nlm.nih.gov/pubmed/12401809?dopt=AbstractPlus]. Unique to both forms of neuropeptide B is the N‐terminal bromination of the first tryptophan residue, and it is from this post‐translational modification that the nomenclature NPB is derived. These peptides were first identified from bovine hypothalamus and therefore are classed as neuropeptides. Endogenous variants of the peptides without the N‐terminal bromination, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1499 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30099, http://www.uniprot.org/uniprot/Q8NG41) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1500 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30099, http://www.uniprot.org/uniprot/Q8NG41), were not found to be major components of bovine hypothalamic tissue extracts. The NPBW2 receptor is activated by the short and C‐terminal extended forms of neuropeptide W and neuropeptide B [http://www.ncbi.nlm.nih.gov/pubmed/12401809?dopt=AbstractPlus].
Comments
Potency measurements were conducted with heterologously‐expressed receptors with a range of 0.14‐0.57 nM (NPBW1) and 0.98‐21 nM (NPBW2).
NPBW1‐/‐ mice show changes in social behavior, suggesting that the NPBW1pathway may have animportant role in theemotional responses of social interaction [http://www.ncbi.nlm.nih.gov/pubmed/21390312?dopt=AbstractPlus].
For a review of the contribution of neuropeptide B/W to social dominance, see Watanabe and Yamamoto, 2015 [http://www.ncbi.nlm.nih.gov/pubmed/26136644?dopt=AbstractPlus]. It has been reported that neuropeptide W may have a key role in the gating of stressful stimuli when mice are exposed to novel environments [http://www.ncbi.nlm.nih.gov/pubmed/27140610?dopt=AbstractPlus].
Two antagonists have been discovered and reported to have affinity for NPBW1, ML181 and ML250, the latter exhibiting improved selectivity (100 fold) for NPBW1 compared to MCH1 receptors [http://www.ncbi.nlm.nih.gov/pubmed/23762933?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22834040?dopt=AbstractPlus]. Computational insights into the binding of antagonists to this receptor have also been described [http://www.ncbi.nlm.nih.gov/pubmed/24938207?dopt=AbstractPlus].
Further reading on Neuropeptide W/neuropeptide B receptors
Sakurai T. (2013) NPBWR1 and NPBWR2: Implications in Energy Homeostasis, Pain, and Emotion. Front Endocrinol (Lausanne) 4: 23 [https://www.ncbi.nlm.nih.gov/pubmed/23515889?dopt=AbstractPlus]
Singh G et al. (2006) Neuropeptide B and W: neurotransmitters in an emerging G‐protein‐coupled receptor system. Br. J. Pharmacol. 148: 1033‐41 [https://www.ncbi.nlm.nih.gov/pubmed/16847439?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=46
Overview
Neuropeptide Y (NPY) receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Neuropeptide Y Receptors [http://www.ncbi.nlm.nih.gov/pubmed/9549761?dopt=AbstractPlus]) are activated by the endogenous peptides http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1504 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7955, http://www.uniprot.org/uniprot/P01303), neuropeptide Y‐(3‐36), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1514 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9748, http://www.uniprot.org/uniprot/P10082), PYY‐(3‐36) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1512 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9327, http://www.uniprot.org/uniprot/P01298) (PP). The receptor originally identified as the Y3 receptor has been identified as the http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=71 (originally named LESTR, [http://www.ncbi.nlm.nih.gov/pubmed/8276799?dopt=AbstractPlus]). The y6 receptor is a functional gene product in mouse, absent in rat, but contains a frame‐shift mutation in primates producing a truncated non‐functional gene [http://www.ncbi.nlm.nih.gov/pubmed/8641440?dopt=AbstractPlus]. Many of the agonists exhibit differing degrees of selectivity dependent on the species examined. For example, the potency of PP is greater at the rat Y4 receptor than at the human receptor [http://www.ncbi.nlm.nih.gov/pubmed/9802391?dopt=AbstractPlus]. In addition, many agonists lack selectivity for individual subtypes, but can exhibit comparable potency against pairs of NPY receptor subtypes, or have not been examined for activity at all subtypes. [125I]‐PYY or [125I]‐NPY can be used to label Y1, Y2, Y5 and y6 subtypes non‐selectively, while [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3921 may be used to label Y5 receptors preferentially (note that cPP denotes chicken peptide sequence and hPP is the human sequence).
Comments
The Y1 agonists indicated are selective relative to Y2 receptors. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1485 is selective relative to Y2, Y4 and Y5 receptors [http://www.ncbi.nlm.nih.gov/pubmed/8700207?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3903) is Y2 selective relative to Y1 and Y5 receptors. PYY‐(3‐36) is Y2 selective relative to Y1 receptors. Note that Pro34‐containing NPY and PYY can also bind Y4 and Y5, thus they are selective only relative to Y2. The y6 receptor is a pseudogene in humans, but is functional in mouse, rabbit and some other mammals.
Further reading on Neuropeptide Y receptors
Bowers ME et al. (2012) Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y. Physiol. Behav. 107: 699‐710 [https://www.ncbi.nlm.nih.gov/pubmed/22429904?dopt=AbstractPlus]
Michel MC et al. (1998) XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY and pancreatic polypeptide receptors. Pharmacol. Rev. 50: 143‐150 [https://www.ncbi.nlm.nih.gov/pubmed/9549761?dopt=AbstractPlus]
Pedragosa‐Badia X et al. (2013) Neuropeptide Y receptors: how to get subtype selectivity. Front En docrinol (Lausanne) 4: 5 [https://www.ncbi.nlm.nih.gov/pubmed/23382728?dopt=AbstractPlus]
Zhang L et al. (2011) The neuropeptide Y system: pathophysiological and therapeutic implications in obesity and cancer. Pharmacol. Ther. 131: 91‐113 [https://www.ncbi.nlm.nih.gov/pubmed/21439311?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=47
Overview
Neurotensin receptors (nomenclature as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) are activated by the endogenous tridecapeptide neurotensin (pGlu‐Leu‐Tyr‐Glu‐Asn‐Lys‐Pro‐Arg‐Arg‐Pro‐Tyr‐Ile‐Leu) derived from a precursor (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8038, http://www.uniprot.org/uniprot/30990), which also generates neuromedin N, an agonist at the NTS2 receptor. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3830) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1574) may be used to label NTS1 and NTS2 receptors at 0.1‐0.3 and 3‐5 nM concentrations respectively.
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1579 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8038, http://www.uniprot.org/uniprot/P30990) appears to be a lowefficacy agonist at the NTS2 receptor [http://www.ncbi.nlm.nih.gov/pubmed/9851594?dopt=AbstractPlus], while the NTS1 receptor antagonist http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1582 is an agonist at NTS2 receptors [http://www.ncbi.nlm.nih.gov/pubmed/9851594?dopt=AbstractPlus]. An additional protein, provisionally termed NTS3 (also known as NTR3, gp95 and sortilin; http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000134243;r=1:109852192‐109940573), has been suggested to bind lipoprotein lipase and mediate its degradation [http://www.ncbi.nlm.nih.gov/pubmed/10085125?dopt=AbstractPlus]. It has been reported to interact with the NTS1 receptor [http://www.ncbi.nlm.nih.gov/pubmed/12360476?dopt=AbstractPlus] and the NTS2 receptor [http://www.ncbi.nlm.nih.gov/pubmed/19891061?dopt=AbstractPlus], and has beenimplicated in hormone trafficking and/or neurotensin uptake. A splice variant of the NTS2 receptor bearing 5 transmembrane domains has been identified in mouse [http://www.ncbi.nlm.nih.gov/pubmed/9001400?dopt=AbstractPlus] and later in rat [http://www.ncbi.nlm.nih.gov/pubmed/15637074?dopt=AbstractPlus].
Further reading on Neurotensin receptors
Boules M et al. (2013) Diverse roles of neurotensin agonists in the central nervous system. Front Endocrinol (Lausanne) 4: 36 https://www.ncbi.nlm.nih.gov/pubmed/23526754?dopt=AbstractPlus
Mazella J et al. (2012) Neurotensin and its receptors in the control of glucose homeostasis. Front Endocrinol (Lausanne) 3: 143 https://www.ncbi.nlm.nih.gov/pubmed/23230428?dopt=AbstractPlus
Myers RM et al. (2009) Cancer, chemistry, and the cell: molecules that interact with the neurotensin receptors. ACS Chem. Biol. 4: 503‐25 https://www.ncbi.nlm.nih.gov/pubmed/19462983?dopt=AbstractPlus
Ouyang Q et al. (2017) Oncogenic role of neurotensin and neurotensin receptors in various cancers. Clin. Exp. Pharmacol. Physiol. 44: 841‐846 https://www.ncbi.nlm.nih.gov/pubmed/28556374?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=50
Overview
Opioid and opioid‐like receptors are activated by a variety of endogenous peptides including [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1614 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8831, http://www.uniprot.org/uniprot/P01210) (met), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1613 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8831, http://www.uniprot.org/uniprot/P01210) (leu), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1643 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9201, http://www.uniprot.org/uniprot/P01189) (β‐end), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3737 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8820, http://www.uniprot.org/uniprot/P01213), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1620 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8820, http://www.uniprot.org/uniprot/P01213) (dynA), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1622 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8820, http://www.uniprot.org/uniprot/P01213) (dynB), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3669 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8820, http://www.uniprot.org/uniprot/P01213) (Big dyn), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1681 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9163, http://www.uniprot.org/uniprot/Q13519) (N/OFQ); http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1623 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3668 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and NC‐IUPHAR considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP. [http://www.ncbi.nlm.nih.gov/pubmed/24528283?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8981566?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]. The human N/OFQ receptor, NOP, is considered ’opioid‐related’ rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [http://www.ncbi.nlm.nih.gov/pubmed/8137918?dopt=AbstractPlus], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1627 and many other opioid analgesics, as well as antagonists such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1638, however only for the μ receptor.
Comments
Three naloxone‐sensitive opioid receptor genes havebeen identified in humans, and while the μ‐receptor in particular may be subject to extensive alternative splicing [http://www.ncbi.nlm.nih.gov/pubmed/24076545?dopt=AbstractPlus], these putative isoforms have not been correlated with any of the subtypesof receptor proposed inyears past. Opioid receptors may heterodimerize with each other or with other 7TM receptors [http://www.ncbi.nlm.nih.gov/pubmed/10385123?dopt=AbstractPlus], and give rise to complexes with a unique pharmacology, however, evidence for such heterodimers in native cells is equivocal and the consequences of this heterodimerization for signalling remains largely unknown. For μ‐opioid receptors at least, dimerization does not seem to be required for signalling [http://www.ncbi.nlm.nih.gov/pubmed/19542234?dopt=AbstractPlus]. A distinct met‐enkephalin receptor lacking structural resemblance to the opioid receptors listed has been identified (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:15768, http://www.uniprot.org/uniprot/9NZT2) and termed an opioid growth factor receptor [http://www.ncbi.nlm.nih.gov/pubmed/11890982?dopt=AbstractPlus].
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1623 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3668 have been identified as highly selective, putative endogenous agonists for the μ‐opioid receptor. At present, however, the mechanisms for endomorphin synthesis in vivo have not been established, and there is no gene identified that encodes for either. Thus, the status of these peptides as endogenous ligands remains unproven.
Two areas of increasing importance in defining opioid receptor function are the presence of functionally relevant single nucleotide polymorphisms in human μ‐receptors [http://www.ncbi.nlm.nih.gov/pubmed/19116204?dopt=AbstractPlus] and the identification of biased signalling by opioid receptor ligands, in particular, compounds previously characterized as antagonists [http://www.ncbi.nlm.nih.gov/pubmed/17702750?dopt=AbstractPlus]. Pathway bias for agonists makes general rank orders of potency and efficacy somewhat obsolete, so these do not appear in the table. As ever, the mechanisms underlying the acute and long term regulation of opiod receptor function are the subject of intense investigation and debate.
The richness of opioid receptor pharmacology has been enhanced with the recent discovery of allosteric modulators of μ and δ receptors, notably thepositive allosteric modulators and silent allosteric “antagonists” outlined in [http://www.ncbi.nlm.nih.gov/pubmed/23754417?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25901762?dopt=AbstractPlus]. Negative allosteric modulation of opioid receptors has been previously suggested [http://www.ncbi.nlm.nih.gov/pubmed/16489449?dopt=AbstractPlus], whether all compounds are acting at a similar site remains to be established.
Further reading on Opioid receptors
Butelman ER et al. (2012) κ‐opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction. Trends Neurosci. 35: 587‐96 https://www.ncbi.nlm.nih.gov/pubmed/22709632?dopt=AbstractPlus
Cox BM et al. (2015) Challenges for opioid receptor nomenclature: IUPHAR Review 9. Br. J. Pharmacol. 172: 317‐23 https://www.ncbi.nlm.nih.gov/pubmed/24528283?dopt=AbstractPlus
Pradhan AA et al. (2011) The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol. Sci. 32: 581‐90 https://www.ncbi.nlm.nih.gov/pubmed/21925742?dopt=AbstractPlus
Williams JT et al. (2013) Regulation of μ‐opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol. Rev. 65: 223‐54 https://www.ncbi.nlm.nih.gov/pubmed/23321159?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=51
Overview
Orexin receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Orexin receptors [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) are activated by the endogenous polypeptides http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1697 (https://www.genenames.org/data/gene‐symbol‐report/%23!/hgnc_id/HGNC:4847, http://www.uniprot.org/uniprot/O43612)and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1699 (https://www.genenames.org/data/gene‐symbol‐report/%23!/hgnc_id/HGNC:4847,http://www.uniprot.org/uniprot/O43612) (also known as hypocretin‐1 and ‐2; 33 and 28 aa) derived from a common precursor, https://www.genenames.org/data/gene‐symbol‐report/%23!/hgnc_id/HGNC:4847, by proteolytic cleavage and some typical peptide modifications [http://www.ncbi.nlm.nih.gov/pubmed/9491897?dopt=AbstractPlus]. Currently the only orexin receptor ligand in clinical use is http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2890,whichisused as a hypnotic. Orexin receptor crystal structures have been solved [http://www.ncbi.nlm.nih.gov/pubmed/26950369?dopt=AbstractPlus,http://www.ncbi.nlm.nih.gov/pubmed/25533960?dopt=AbstractPlus].
Comments
The primary coupling of orexin receptors to Gq/11 proteins is rather speculative and based on the strong activation of phospholipase C, though recent studies in recombinant cells also stress the importance of Gq/11 [http://www.ncbi.nlm.nih.gov/pubmed/27237973?dopt=AbstractPlus]. Coupling of both receptors to Gi/o and Gs has also been reported [http://www.ncbi.nlm.nih.gov/pubmed/15687100?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23902572?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23848055?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11600545?dopt=AbstractPlus]. For most native cellular responses observed, the G protein pathway is unknown. The relative potency order of endogenous ligands depends on the cellular signal transduction machinery [http://www.ncbi.nlm.nih.gov/pubmed/23034387?dopt=AbstractPlus]. Similarly, [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1700, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1700]http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1700, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9305 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10277 may show variable selectivity for OX2 receptors and are also likely to activate OX1 receptors [http://www.ncbi.nlm.nih.gov/pubmed/21362456?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/30194937?dopt=AbstractPlus]. Many antagonists and radioligands are not well‐characterized, and thus the affinities are uncertain. Among radioligands, [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1706 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1706, [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9467 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9467 and [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9465 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9465 are commercially available. [3H]‐TCS 1102 (pKd/OX1 8.2, pKd/OX2 9.0) [http://www.ncbi.nlm.nih.gov/pubmed/24376396?dopt=AbstractPlus] and Rhodamine Green‐orexinA [http://www.ncbi.nlm.nih.gov/pubmed/11266181?dopt=AbstractPlus] are also useful radioligand tools. Orexin receptors have been reported to be able to form complexes with each other and some other GPCRs as well as σ1 receptors, which might affect the signaling and pharmacology [http://www.ncbi.nlm.nih.gov/pubmed/27909990?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25926444?dopt=AbstractPlus]. Loss‐of‐function mutations in the gene encoding the OX2 receptor underlie canine hereditary narcolepsy [http://www.ncbi.nlm.nih.gov/pubmed/10458611?dopt=AbstractPlus]. Antagonists of the orexin receptors are the focus of major drug discovery efforts for their potential to treat insomnia and other disorders of wakefulness [http://www.ncbi.nlm.nih.gov/pubmed/26317591?dopt=AbstractPlus], while agonists would likely be useful in human narcolepsy.
Further reading on Orexin receptors
Baimel C et al. (2015) Orexin/hypocretin role in reward: implications for opioid and other addictions. Br. J. Pharmacol. 172: 334‐48 [https://www.ncbi.nlm.nih.gov/pubmed/24641197?dopt=AbstractPlus]
Burdakov D. (2018) Reactive and predictive homeostasis: Roles of orexin/hypocretin neurons. Neuropharmacology [https://www.ncbi.nlm.nih.gov/pubmed/30347195?dopt=AbstractPlus]
Kukkonen JP. (2013) Physiology of the orexinergic/hypocretinergic system: a revisit in 2012. Am. J. Physiol., Cell Physiol. 304: C2‐32 [https://www.ncbi.nlm.nih.gov/pubmed/23034387?dopt=AbstractPlus]
Li SB et al. (2016) Hypocretins, Neural Systems, Physiology, and Psychiatric Disorders. Curr Psychiatry Rep 18: 7 [https://www.ncbi.nlm.nih.gov/pubmed/26733323?dopt=AbstractPlus]
Mahler SV et al. (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat. Neurosci. 17: 1298‐303 [https://www.ncbi.nlm.nih.gov/pubmed/25254979?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=447
Overview
Nomenclature as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/23686350?dopt=AbstractPlus].
Further reading on Oxoglutarate receptor
Davenport AP et al. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein‐coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol. Rev. 65: 967‐86 [https://www.ncbi.nlm.nih.gov/pubmed/23686350?dopt=AbstractPlus]
Grimm PR and Welling PA (2017) alpha‐Ketoglutarate drives electroneutral NaCl reabsorption in intercalated cells by activating a G‐protein coupled receptor. Oxgr1. Curr. Opin. Nephrol. Hypertens. 26: 426‐433 [https://www.ncbi.nlm.nih.gov/pubmed/28771454]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=52
Overview
P2Y receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on P2Y Receptors [http://www.ncbi.nlm.nih.gov/pubmed/12559763?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16968944?dopt=AbstractPlus]) are activated by the endogenous ligands http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1712, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1734, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1749 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1783. The relationship of many of the cloned receptors to endogenously expressed receptors is not yet established and so it might be appropriate to use wording such as ’http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1734‐preferring (or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713‐, etc.) P2Y receptor’ or ’P2Y1‐like’, etc., until further, as yet undefined, corroborative criteria can be applied [271, http://www.ncbi.nlm.nih.gov/pubmed/21586366?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23597047?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21586365?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22963441?dopt=AbstractPlus]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1736, agonist of the P2Y2 receptor subtype, approved in Japan for the management of dry eye disease [http://www.ncbi.nlm.nih.gov/pubmed/24511227?dopt=AbstractPlus], and the P2Y12 receptor antagonists http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7562, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1765 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1776, all approved as antiplatelet drugs [http://www.ncbi.nlm.nih.gov/pubmed/23809135?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/27886821?dopt=AbstractPlus].
Comments
A series of 4‐alkyloxyimino derivatives of uridine5’‐triphosphate which could be useful for derivatization as fluorescent P2Y2/4/6 receptor probes has been recently synthesized [http://www.ncbi.nlm.nih.gov/pubmed/24712832?dopt=AbstractPlus].
Single nucleotide polymorphisms of the P2YR1 gene have been associated to different platelet reactivity to ADP http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1712 [http://www.ncbi.nlm.nih.gov/pubmed/15514209?dopt=AbstractPlus]. Three frequent nonsynonymous P2Y2 receptor polymorphisms have been identified, one of which was significantly more common in cystic fibrosis patients. This polymorphism is linked to increases in Ca2+ influx in transfected cells, and might therefore play a role in disease development [http://www.ncbi.nlm.nih.gov/pubmed/16495779?dopt=AbstractPlus]. Although http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1734 (UTP) was also shown to be a biased agonist at P2Y11, this is still under debate [http://www.ncbi.nlm.nih.gov/pubmed/25015314?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12761346?dopt=AbstractPlus]. A group of single nucleotide polymorphisms in the P2Y12 gene, forming the so called P2Y12 H2 haplotype, has been associated with increased platelet responsiveness to ADP, increased risk of peripheral arterial disease and with coronary artery disease [http://www.ncbi.nlm.nih.gov/pubmed/17803810?dopt=AbstractPlus]. The platelet‐type bleeding disorder due to P2Y12 receptor defects is an autosomal recessive condition characterized by mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma. The defect is due to the inability of ADP to induce platelet aggregation [http://www.ncbi.nlm.nih.gov/pubmed/12578987?dopt=AbstractPlus]. The P2Y13 receptor Met‐158‐Thr polymorphism, which is in linkage disequilibrium with the P2Y12 locus, is not associated with acute myocardial infarction, diabetes mellitus or related risk factors [http://www.ncbi.nlm.nih.gov/pubmed/18213371?dopt=AbstractPlus]. The P2Y14 receptor was previously considered to exclusively bind sugar nucleotides such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1783 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1782 [http://www.ncbi.nlm.nih.gov/pubmed/10753868?dopt=AbstractPlus]. However, more recent evidence with several cell lines has demonstrated that http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1749 (UDP) is 5‐fold more potent than http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1783 [http://www.ncbi.nlm.nih.gov/pubmed/19759354?dopt=AbstractPlus]. UDP was also shown to competitively antagonise the UDP‐glucose response at the human recombinant P2Y14 receptor [http://www.ncbi.nlm.nih.gov/pubmed/18252808?dopt=AbstractPlus].
Further reading on P2Y receptors
Abbracchio MP et al. (2006) International Union of Pharmacology LVIII: update on the P2Y G protein‐coupled nucleotide receptors: frommolecular mechanisms andpathophysiology totherapy. Pharmacol. Rev. 58: 281‐341 [https://www.ncbi.nlm.nih.gov/pubmed/16968944?dopt=AbstractPlus]
Jacobson KA et al. (2015) Nucleotides Acting at P2Y Receptors: Connecting Structure and Function. Mol. Pharmacol. 88: 220‐30 [https://www.ncbi.nlm.nih.gov/pubmed/25837834?dopt=AbstractPlus]
von Kügelgen I et al. (2016) Pharmacology and structure of P2Y receptors. Neuropharmacology 104: 50‐61 [https://www.ncbi.nlm.nih.gov/pubmed/26519900?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=53
Overview
The parathyroid hormone receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Parathyroid Hormone Receptors [http://www.ncbi.nlm.nih.gov/pubmed/25713287?dopt=AbstractPlus]) are family B G protein‐coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone‐related peptide (PTHrP) receptor (PTH1 receptor) is activated by precursor‐derived peptides: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1785 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9606, http://www.uniprot.org/uniprot/P01270) (84 amino acids), and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3738 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9607, http://www.uniprot.org/uniprot/P12272) (141 amino‐acids) and related peptides (PTH‐(1‐34), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1790, http://www.uniprot.org/uniprot/P12272)). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor‐derived peptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1815 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30828, http://www.uniprot.org/uniprot/Q96A98) (39 amino acids). [125I]PTH may be used to label both PTH1 and PTH2 receptors.
Comments
The parathyroid hormone type 1 receptor (PTHR) is the canonical GPCR for PTH and PTHrP. It is coupled to Gs and Gq and regulates the development of bone, heart, mammary glands and other tissues in response to PTHrP, and blood concentrations of calcium and phosphate ions, as well as vitamin D, in response to PTH. Another important action of the PTH/PTHR system is to stimulate bone formation when the hormone is intermittently administrated (daily injection).
Although http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1785 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9606, http://www.uniprot.org/uniprot/P01270) is an agonist at human PTH2 receptors, it fails to activate the rodent orthologues. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1815 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30828, http://www.uniprot.org/uniprot/Q96A98) is a weak antagonist at PTH1 receptors [http://www.ncbi.nlm.nih.gov/pubmed/11159842?dopt=AbstractPlus].
Further reading on Parathyroid hormone receptors
Cheloha RW et al. (2015) PTH receptor‐1 signalling‐mechanistic insights and therapeutic prospects. Nat Rev Endocrinol 11: 712‐24 [https://www.ncbi.nlm.nih.gov/pubmed/26303600?dopt=AbstractPlus]
Gardella TJ et al. (2015) International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors‐Family B G Protein‐Coupled Receptors. Pharmacol. Rev. 67: 310‐37 [https://www.ncbi.nlm.nih.gov/pubmed/25713287?dopt=AbstractPlus]
Vilardaga JP et al. (2014) Endosomal generation of cAMP in GPCR signaling. Nat. Chem. Biol. 10: 700‐6 [https://www.ncbi.nlm.nih.gov/pubmed/25271346?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=55
Overview
Platelet‐activating factor (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1831, 1‐O‐alkyl‐2‐acetyl‐sn‐glycero‐3‐phosphocholine) is an ether phospholipid mediator associated with platelet coagulation, but also subserves inflammatory roles. The PAF receptor (provisional nomenclature recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) is activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1831 and other suggested endogenous ligands are oxidized phosphatidylcholine [http://www.ncbi.nlm.nih.gov/pubmed/10497200?dopt=AbstractPlus] and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2508 [http://www.ncbi.nlm.nih.gov/pubmed/9038918?dopt=AbstractPlus]. It may also be activated by bacterial lipopolysaccharide [http://www.ncbi.nlm.nih.gov/pubmed/1333988?dopt=AbstractPlus].
Comments
Note that a previously recommended radioligand (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1859 Kd 44.6 nM) is currently unavailable.
Further reading on Platelet‐activating factor receptor
Foord SM et al. (2005) International Union of Pharmacology. XLVI. G protein‐coupled receptor list. Pharmacol Rev 57: 279‐288 [https://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]
Ishii S et al. (2000) Platelet‐activating factor (PAF) receptor and genetically engineered PAF receptor mutant mice. Prog. Lipid Res. 39: 41‐82 [https://www.ncbi.nlm.nih.gov/pubmed/10729607?dopt=AbstractPlus]
Prescott SM et al. (2000) Platelet‐activating factor and related lipid mediators. Annu. Rev. Biochem. 69: 419‐45 [https://www.ncbi.nlm.nih.gov/pubmed/10966465?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=56
Overview
Prokineticin receptors, PKR1 and PKR2 (provisional nomenclature as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) respond to the cysteine‐rich 81‐86 amino‐acid peptides http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1866 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18454, http://www.uniprot.org/uniprot/Q9HC23) (also known as endocrine glandderived vascular endothelial growth factor, mambakine) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1867 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18455, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:18455) (protein Bv8 homologue). An orthologue of PROK1 from black mamba (Dendroaspis polylepis) venom, mamba intestinal toxin 1 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1865, [http://www.ncbi.nlm.nih.gov/pubmed/10567694?dopt=AbstractPlus]) is a potent, nonselective agonist at prokineticin receptors [http://www.ncbi.nlm.nih.gov/pubmed/12054613?dopt=AbstractPlus], while http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5362, an orthologue of PROK2 from amphibians (Bombina sp., [http://www.ncbi.nlm.nih.gov/pubmed/10422759?dopt=AbstractPlus]), is equipotent at recombinant PKR1 and PKR2 [http://www.ncbi.nlm.nih.gov/pubmed/16113687?dopt=AbstractPlus], and has high potency in macrophagechemotaxis assays, which arelost in PKR1null mice.
Comments
Genetic mutations in PROKR1 are associated with Hirschsprung's disease [http://www.ncbi.nlm.nih.gov/pubmed/21858136?dopt=AbstractPlus], while genetic mutations in PROKR2 are associated with hypogonadotropic hypogonadism with anosmia [http://www.ncbi.nlm.nih.gov/pubmed/23596439?dopt=AbstractPlus], hypopituitarism with pituitary stalk interruption [http://www.ncbi.nlm.nih.gov/pubmed/22466334?dopt=AbstractPlus] and Hirschsprung's disease [http://www.ncbi.nlm.nih.gov/pubmed/21858136?dopt=AbstractPlus]. PKR2 has been recently identified as a receptor for T. cruzi natural infection [http://www.ncbi.nlm.nih.gov/pubmed/25324134?dopt=AbstractPlus].
Further reading on Prokineticin receptors
Boulberdaa M et al. (2011) Prokineticin receptor 1 (PKR1) signalling in cardiovascular and kidney functions. Cardiovasc. Res. 92: 191‐8 [https://www.ncbi.nlm.nih.gov/pubmed/21856786?dopt=AbstractPlus]
Negri L et al. (2018) The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell‐Dependent Angiogenesis. Physiol. Rev. 98: 1055‐1082 [https://www.ncbi.nlm.nih.gov/pubmed/29537336?dopt=AbstractPlus]
Negri L et al. (2012) Bv8/PK2 and prokineticin receptors: a druggable pronociceptive system. Curr Opin Pharmacol 12: 62‐6 [https://www.ncbi.nlm.nih.gov/pubmed/22136937?dopt=AbstractPlus]
Negri L et al. (2007) Bv8/Prokineticin proteins and their receptors. Life Sci. 81: 1103‐16 [https://www.ncbi.nlm.nih.gov/pubmed/17881008?dopt=AbstractPlus]
Ngan ES et al. (2008) Prokineticin‐signaling pathway. Int. J. Biochem. Cell Biol. 40: 1679‐84 [https://www.ncbi.nlm.nih.gov/pubmed/18440852?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=57
Overview
The precursor (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:17945, http://www.uniprot.org/uniprot/P81277) for PrRP generates 31 and 20‐amino‐acid versions. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3665 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:29982, http://www.uniprot.org/uniprot/P83859) (named after a pyroglutamylated arginine‐phenylalanine‐amide peptide) is a 43 amino acid peptide derived from https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:29982 (http://www.uniprot.org/uniprot/P83859) and is also known as P518 or 26RFa. RFRP is an RF amide‐related peptide [http://www.ncbi.nlm.nih.gov/pubmed/11025660?dopt=AbstractPlus] derived from a FMRFamide‐related peptide precursor (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:13782, http://www.uniprot.org/uniprot/Q9HCQ7), which is cleaved to generate http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3736 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7901, http://www.uniprot.org/uniprot/O15130), neuropeptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5340 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:13782, http://www.uniprot.org/uniprot/Q9HCQ7), neuropeptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5373 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:13782, http://www.uniprot.org/uniprot/Q9HCQ7) and neuropeptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4016 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:13782, http://www.uniprot.org/uniprot/Q9HCQ7) (neuropeptide NPVF).
Comments
The orphan receptor https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4523 (http://www.uniprot.org/uniprot/Q9NYM4) shows sequence similarities with NPFF1, NPFF2, PrRP and QRFP receptors.
Further reading on Prolactin‐releasing peptide receptor
Samson WK et al. (2006) Prolactin releasing peptide (PrRP): an endogenous regulator of cell growth. Peptides 27: 1099‐103 [https://www.ncbi.nlm.nih.gov/pubmed/16500730?dopt=AbstractPlus]
Takayanagi Y et al. (2010) Roles of prolactin‐releasing peptide and RFamide related peptides in the control of stress and food intake. FEBS J. 277: 4998‐5005 [https://www.ncbi.nlm.nih.gov/pubmed/21126313?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=58
Overview
Prostanoid receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Prostanoid Receptors [http://www.ncbi.nlm.nih.gov/pubmed/21752876?dopt=AbstractPlus]) are activated by the endogenous ligands prostaglandins http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1881, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1882, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1883, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1884, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4483, prostacyclin [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1915] and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4482. Measurement of the potency of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1915 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4482 is hampered by their instability in physiological salt solution; they are often replaced by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1917 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1888, respectively, in receptor characterization studies.
Comments
Whilst http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1917 is selective for IP receptors, it does exhibit moderate agonist potency at EP4 receptors [http://www.ncbi.nlm.nih.gov/pubmed/10634944?dopt=AbstractPlus]. Apart from IP receptors, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1895 also binds to EP1 receptors.
The EP1 agonist http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1912 also shows agonist activity at EP3 and EP4 receptors [http://www.ncbi.nlm.nih.gov/pubmed/21323896?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/27664754?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3379 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3331 may require de‐esterification within tissues to attain full agonist potency. There is evidence for subtypes of FP [http://www.ncbi.nlm.nih.gov/pubmed/7830272?dopt=AbstractPlus] and TP receptors [http://www.ncbi.nlm.nih.gov/pubmed/8882612?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8034687?dopt=AbstractPlus]. mRNA for the EP3 receptor undergoes alternative splicing to produce variants which can interfere with signalling [http://www.ncbi.nlm.nih.gov/pubmed/8940129?dopt=AbstractPlus] or generate complex patterns of G‐protein (Gi/o, Gq/11, Gs and G12,13) coupling (e.g. [http://www.ncbi.nlm.nih.gov/pubmed/7476918?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7608175?dopt=AbstractPlus]). The number of EP3 receptor (protein) variants are variable depending on species, with five in human, three in rat and three in mouse. Putative receptor(s) for prostamide F (which as yet lack molecular correlates) and which preferentially recognize http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5456 and its analogues (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1958) have been identified, together with moderate‐potency antagonists (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5455) [http://www.ncbi.nlm.nih.gov/pubmed/18700152?dopt=AbstractPlus].
The free acid form of AL‐12182, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3386, used in in vitro studies, has a EC50 of 15nM which is the concentration of the compound giving half‐maximal stimulation of inositol phosphate turnover in HEK‐293 cells expressing the human FP receptor [http://www.ncbi.nlm.nih.gov/pubmed/17076623?dopt=AbstractPlus].
References given alongside the TP receptor agonists I‐BOP [http://www.ncbi.nlm.nih.gov/pubmed/1830308?dopt=AbstractPlus] and STA2 [http://www.ncbi.nlm.nih.gov/pubmed/8242228?dopt=AbstractPlus] use human platelets as the source of TP receptors for competition radio‐ligand binding assays to determine the indicated activity values.
Pharmacological evidence for a second IP receptor, denoted IP2, in the central nervous system [http://www.ncbi.nlm.nih.gov/pubmed/8621463?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10349870?dopt=AbstractPlus] and in the BEAS‐2B human airway epithelial cell line [http://www.ncbi.nlm.nih.gov/pubmed/21173040?dopt=AbstractPlus] is available. This receptor is selectively activated by 15R‐17,18,19,20‐tetranor‐16‐m‐tolylisocarbacyclin (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5864) and 15R‐Deoxy 17,18,19,20‐tetranor‐16m‐tolyl‐isocarbacyclin (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5865). However, molecular biological evidence for an IP2 subtype is currently lacking.
Further reading on Prostanoid receptors
Woodward DF et al. (2011) International union of basic and clinical pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress. Pharmacol. Rev. 63: 471‐538 [https://www.ncbi.nlm.nih.gov/pubmed/21752876?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=59
Overview
Proteinase‐activated receptors (PARs, nomenclature as agreed by the NC‐IUPHAR Subcommittee on Proteinase‐activated Receptors [http://www.ncbi.nlm.nih.gov/pubmed/12037136?dopt=AbstractPlus]) are unique members of the GPCR superfamily activated by proteolytic cleavage of their amino terminal exodomains. Agonist proteinase‐induced hydrolysis unmasks a tethered ligand (TL) at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. TL sequences at human PAR1‐4 are http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5361, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3740, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5360 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3739, respectively. With the exception of PAR3, synthetic peptides with these sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors. Several proteinases, including neutrophil elastase, cathepsin G and chymotrypsin can have inhibitory effects at PAR1 and PAR2 such that they cleave the exodomain of the receptor without inducing activation of Gαq‐coupled calcium signalling, thereby preventing activation by activating proteinases but not by agonist peptides. Neutrophil elastase (NE) cleavage of PAR1 and PAR2 can however activate MAP kinase signaling by exposing a TL that is different from the one revealed by trypsin [http://www.ncbi.nlm.nih.gov/pubmed/22212680?dopt=AbstractPlus]. PAR2 ectivation by NE regulates inflammation and pain responses [http://www.ncbi.nlm.nih.gov/pubmed/26140667?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25878251?dopt=AbstractPlus] and triggers mucin secretion from airway epithelial cells [http://www.ncbi.nlm.nih.gov/pubmed/23392769?dopt=AbstractPlus].
Comments
Endogenous serine proteases (EC 3.4.21.) active at the proteinase‐activated receptors include: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4453 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3535, http://www.uniprot.org/uniprot/P00734), generated by the action of Factor X (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3528, http://www.uniprot.org/uniprot/P00742) on liver‐derived prothrombin (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3535, http://www.uniprot.org/uniprot/P00734); trypsin, generated by the action of enterokinase (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9490, http://www.uniprot.org/uniprot/P98073) on pancreatic‐derived trypsinogen (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9475, http://www.uniprot.org/uniprot/P07477); tryptase, a family of enzymes (α/β1 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12019, http://www.uniprot.org/uniprot/Q15661; γ1 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:14134, http://www.uniprot.org/uniprot/Q9NRR2 δ1 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:14118, http://www.uniprot.org/uniprot/Q9BZJ3) secreted from mast cells; cathepsin G (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2532, http://www.uniprot.org/uniprot/P08311) generated from leukocytes; liver‐derived protein C (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9451, http://www.uniprot.org/uniprot/P04070) generated in plasma by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4453 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3535, http://www.uniprot.org/uniprot/P00734) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6655 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7155, http://www.uniprot.org/uniprot/P45452).
Further reading on Proteinase‐activated receptors
Adams MN et al. (2011) Structure, function and pathophysiology of protease activated receptors. Pharmacol. Ther. 130: 248‐82 https://www.ncbi.nlm.nih.gov/pubmed/21277892?dopt=AbstractPlus
Canto I et al. (2012) Allosteric modulation of protease‐activated receptor signaling. Mini Rev Med Chem 12: 804‐11 https://www.ncbi.nlm.nih.gov/pubmed/22681248?dopt=AbstractPlus
García PS et al. (2010) The role of thrombin and protease‐activated receptors in pain mechanisms. Thromb. Haemost. 103: 1145‐51 https://www.ncbi.nlm.nih.gov/pubmed/20431855?dopt=AbstractPlus
Hollenberg MD et al. (2002) International Union of Pharmacology. XXVIII. Proteinase‐activated receptors. Pharmacol. Rev. 54: 203‐17 https://www.ncbi.nlm.nih.gov/pubmed/12037136?dopt=AbstractPlus
Ramachandran R et al. (2012) Targeting proteinase‐activated receptors: therapeutic potential and challenges. Nat Rev Drug Discov 11: 69‐86 https://www.ncbi.nlm.nih.gov/pubmed/22212680?dopt=AbstractPlus
Soh UJ et al. (2010) Signal transduction by protease‐activated receptors. Br. J. Pharmacol. 160: 191‐203 https://www.ncbi.nlm.nih.gov/pubmed/20423334?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=54
Overview
The human gene encoding the QRFP receptor (nomenclature as agreed by the NC‐IUPHAR Subcommittee on the QRFP receptor [http://www.ncbi.nlm.nih.gov/pubmed/28613414?dopt=AbstractPlus]; QRFPR, formerly known as the Peptide P518 receptor), previously designated as an orphan GPCR receptor was identified in 2001 by Lee et al. from a hypothalamus cDNA library [http://www.ncbi.nlm.nih.gov/pubmed/11574155?dopt=AbstractPlus]. However, the reported cDNA (AF411117) is a chimera with bases 1‐127 derived from chromosome 1 and bases 155‐1368 derived from chromosome 4. When corrected, QRFPR (also referred to as SP9155 or AQ27) encodes a 431 amino acid protein that shares sequence similarities in the transmembrane spanning regions with other peptide receptors. These include neuropeptide FF2 (38%), neuropeptide Y2 (37%) and galanin Gal1 (35%) receptors.
Comments
The orphan receptor http://www.guidetopharmacology.org/GRAC/ (http://www.uniprot.org/uniprot/9NYM4) shows sequence similarities with the QRFP receptor, as well as with the NPFF1, NPFF2, and PrRP receptors.
Further reading on QRFP receptor
Chartrel N et al. (2011) The RFamide neuropeptide 26RFa and its role in the control of neuroendocrine functions. Front Neuroendocrinol 32: 387‐97 https://www.ncbi.nlm.nih.gov/pubmed/21530572?dopt=AbstractPlus
Fukusumi S et al. (2006) Recent advances in mammalian RFamide peptides: the discovery and functional analyses of PrRP, RFRPs and QRFP. Peptides 27: 1073‐86 https://www.ncbi.nlm.nih.gov/pubmed/16500002?dopt=AbstractPlus
Leprince J et al. (2017) The Arg‐Phe‐amide peptide 26RFa/glutamine RF‐amide peptide and its receptor: IUPHAR Review 24. Br. J. Pharmacol. 174: 3573‐3607 https://www.ncbi.nlm.nih.gov/pubmed/28613414?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=60
Overview
Relaxin family peptide receptors (RXFP, nomenclature as agreed by the NC‐IUPHAR Subcommittee on Relaxin family peptide receptors [http://www.ncbi.nlm.nih.gov/pubmed/16507880?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25761609?dopt=AbstractPlus]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1988 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10026, http://www.uniprot.org/uniprot/P04808), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1989 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10027, http://www.uniprot.org/uniprot/P04090), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1990 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:17135, http://www.uniprot.org/uniprot/Q8WXF3) (also known as INSL7), insulin‐like peptide 3 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1995 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6086, http://www.uniprot.org/uniprot/P51460)) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2000 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6088, http://www.uniprot.org/uniprot/Q9Y5Q6). Species homologues of relaxin have distinct pharmacology and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1989 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10027, http://www.uniprot.org/uniprot/P04090) interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [http://www.ncbi.nlm.nih.gov/pubmed/15956680?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1990 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:17135, http://www.uniprot.org/uniprot/Q8WXF3) is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [http://www.ncbi.nlm.nih.gov/pubmed/15956681?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2000 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6088, http://www.uniprot.org/uniprot/Q9Y5Q6) is the ligand for RXFP4 but is a weak antagonist of RXFP3. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1989 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10027, http://www.uniprot.org/uniprot/P04090) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1995 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6086, http://www.uniprot.org/uniprot/P51460) have multiple complex binding interactions with RXFP1 [http://www.ncbi.nlm.nih.gov/pubmed/27088579?dopt=AbstractPlus] and RXFP2 [http://www.ncbi.nlm.nih.gov/pubmed/30594862?dopt=AbstractPlus] which direct the N‐terminal LDLa modules of the receptors together with a linker domain to act as a tethered ligand to direct receptor signaling [http://www.ncbi.nlm.nih.gov/pubmed/16963451?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2000 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6088, http://www.uniprot.org/uniprot/Q9Y5Q6) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1990 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:17135, http://www.uniprot.org/uniprot/Q8WXF3) interact with their receptors using distinct residues in their B‐chains for binding, and activation, respectively [http://www.ncbi.nlm.nih.gov/pubmed/28274616?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/30131340?dopt=AbstractPlus].
Comments
http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1989 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10027, http://www.uniprot.org/uniprot/P04090) is the cognate peptide ligand for RXFP1 and is in extended Phase III clinical trials for the treatment of acute heart failure [http://www.ncbi.nlm.nih.gov/pubmed/23273292?dopt=AbstractPlus]. Relaxin has vasodilatory, anti‐fibrotic, angiogenic, anti‐apoptotic and anti‐inflammatory effects. A small molecule allosteric agonists http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8322 has been developed [http://www.ncbi.nlm.nih.gov/pubmed/18854305?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23764525?dopt=AbstractPlus], and a relaxin B‐chain mimetic peptide B7‐33 has been developed which that has cell specific signaling properties [http://www.ncbi.nlm.nih.gov/pubmed/30155023?dopt=AbstractPlus]. The antifibrotic actions of relaxin are dependent on the angiotensin receptor AT2 [http://www.ncbi.nlm.nih.gov/pubmed/24429402?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1995 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6086, http://www.uniprot.org/uniprot/P51460) is the cognate peptide for RXFP2 and is a circulating hormone that in males is essential for testicular descent in utero [http://www.ncbi.nlm.nih.gov/pubmed/10391220?dopt=AbstractPlus] and in females has important roles in ovarian follicle function [http://www.ncbi.nlm.nih.gov/pubmed/30204868?dopt=AbstractPlus]. In adults, INSL3 has potential roles in testicular function [http://www.ncbi.nlm.nih.gov/pubmed/20952422?dopt=AbstractPlus] and the musculoskeletal system [http://www.ncbi.nlm.nih.gov/pubmed/30625346?dopt=AbstractPlus]. RXFP2 is also present in brain, associated with cortico‐thalamic motor circuits [http://www.ncbi.nlm.nih.gov/pubmed/18706979?dopt=AbstractPlus]. cAMP elevation is the major signalling pathway for both RXFP1 and RXFP2 [http://www.ncbi.nlm.nih.gov/pubmed/10935549?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/11809971?dopt=AbstractPlus], but RXFP1 also activates MAP kinases, nitric oxide signalling, and tyrosine kinase phosphorylation; and relaxin can interact with glucocorticoid receptors [http://www.ncbi.nlm.nih.gov/pubmed/17293890?dopt=AbstractPlus]. Receptor expression profiles suggest that RXFP3 is a brain neuropeptide receptor and RXFP4 a gut hormone receptor. The brain relaxin‐3/RXFP3 system modulates feeding [http://www.ncbi.nlm.nih.gov/pubmed/23135160?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22854307?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21384867?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22257012?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21899720?dopt=AbstractPlus] via effects in hypothalamus [http://www.ncbi.nlm.nih.gov/pubmed/28864207?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/23135160?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/28098344?dopt=AbstractPlus], anxiety [http://www.ncbi.nlm.nih.gov/pubmed/24297931?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26057358?dopt=AbstractPlus], reward and motivated, goal‐directed behaviours [http://www.ncbi.nlm.nih.gov/pubmed/25257104?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24297931?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25849482?dopt=AbstractPlus], and spatial and social memory [http://www.ncbi.nlm.nih.gov/pubmed/30368554?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/28100033?dopt=AbstractPlus]. Of the other relaxin peptides, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1990 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:17135, http://www.uniprot.org/uniprot/Q8WXF3)is anagonist atRXFP3 and RXFP4 whereashttp://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2000 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6088, http://www.uniprot.org/uniprot/Q9Y5Q6) is an agonist at RXFP4 and a weak antagonist at RXFP3. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2000 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6088, http://www.uniprot.org/uniprot/Q9Y5Q6) is secreted from enteroendocrine L cells and the INSL5/RXFP4 system affects food intake [http://www.ncbi.nlm.nih.gov/pubmed/25028498?dopt=AbstractPlus] and glucose homeostasis [http://www.ncbi.nlm.nih.gov/pubmed/25514935?dopt=AbstractPlus]. RXFP3 and RXFP4 couple to Gi/o and inhibit adenylyl cyclase [http://www.ncbi.nlm.nih.gov/pubmed/14522968?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20159943?dopt=AbstractPlus], and also cause Erk1/2 phosphorylation [http://www.ncbi.nlm.nih.gov/pubmed/20159943?dopt=AbstractPlus]. RXFP4 also causes phosphorylation of p38MAPK, Akt and S6RP [http://www.ncbi.nlm.nih.gov/pubmed/27243554?dopt=AbstractPlus] and GLP‐1 secretion in vitro [http://www.ncbi.nlm.nih.gov/pubmed/29535183?dopt=AbstractPlus]. There is evidence that at RXFP3, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1989 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10027, http://www.uniprot.org/uniprot/P04090) is a biased ligand compared to the cognate ligand http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1990 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:17135, http://www.uniprot.org/uniprot/Q8WXF3) [http://www.ncbi.nlm.nih.gov/pubmed/20159943?dopt=AbstractPlus].
Further reading on Relaxin family peptide receptors
Bathgate RA et al. (2013) Relaxin family peptides and their receptors. Physiol. Rev. 93: 405‐80 https://www.ncbi.nlm.nih.gov/pubmed/23303914?dopt=AbstractPlus
Du XJ et al. (2010) Cardiovascular effects of relaxin: from basic science to clinical therapy. Nat Rev Cardiol 7: 48‐58 https://www.ncbi.nlm.nih.gov/pubmed/19935741?dopt=AbstractPlus
Halls ML et al. (2015) International Union of Basic and Clinical Pharmacology. XCV. Recent advances in the understanding of the pharmacology and biological roles of relaxin family peptide receptors 1‐4, the receptors for relaxin family peptides. Pharmacol. Rev. 67: 389‐440 https://www.ncbi.nlm.nih.gov/pubmed/25761609?dopt=AbstractPlus
Ivell R etal. (2011) Relaxin family peptides in the male reproductive system‐a critical appraisal. Mol. Hum. Reprod. 17: 71‐84 https://www.ncbi.nlm.nih.gov/pubmed/20952422?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=61
Overview
Somatostatin (somatotropin release inhibiting factor) is an abundant neuropeptide, which acts on five subtypes of somatostatin receptor (SST1‐SST5; nomenclature as agreed by the NC‐IUPHAR Subcommittee on Somatostatin Receptors [http://www.ncbi.nlm.nih.gov/pubmed/30232095?dopt=AbstractPlus]). Activation of these receptors produces a wide range of physiological effects throughout the body including the inhibition of secretion of many hormones. Endogenous ligands for these receptors are somatostatin‐14 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2019 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11329, http://www.uniprot.org/uniprot/P61278)) and somatostatin‐28 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2020 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11329, http://www.uniprot.org/uniprot/P61278)). http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2007 {Mouse, Rat} has also been suggested to be an endogenous ligand for somatostatin receptors [http://www.ncbi.nlm.nih.gov/pubmed/8622767?dopt=AbstractPlus].
Comments
[http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2060, [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2023, [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2022 and [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2024 may be used to label somatostatin receptors nonselectively. A number of nonpeptide subtype‐selective agonists have been synthesised [http://www.ncbi.nlm.nih.gov/pubmed/9784130?dopt=AbstractPlus]. Octreotide and lanreotide are being used in the treatment of SST2‐expressing neuroendocrine tumors and pasireotide for SST5‐expressing neuroendocrine tumors. A novel peptide somatostatin analogue, veldoreotide (COR‐005), has affinity for SST2, SST4 and SST5 receptors and is a potent inhibitor of GH secretion [http://www.ncbi.nlm.nih.gov/pubmed/22065857?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15636423?dopt=AbstractPlus].
Further reading on Somatostatin receptors
Colao A et al. (2011) Resistance to somatostatin analogs in acromegaly. Endocr. Rev. 32: 247‐71 https://www.ncbi.nlm.nih.gov/pubmed/21123741?dopt=AbstractPlus
Günther T et al. (2018) International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature. Pharmacol. Rev. 70: 763‐835 https://www.ncbi.nlm.nih.gov/pubmed/30232095?dopt=AbstractPlus
Hoyer D et al. (2000) Somatostatin receptors. In The IUPHAR Compendium of Receptor Characterization and Classification, 2nd edn. Edited by Watson SP, Girdlestone D: IUPHAR Media: 354‐364
Schulz S et al. (2014) Fine‐tuning somatostatin receptor signalling by agonist‐selective phosphorylation and dephosphorylation: IUPHAR Review 5. Br. J. Pharmacol. 171: 1591‐9 https://www.ncbi.nlm.nih.gov/pubmed/24328848?dopt=AbstractPlus
Weckbecker G et al. (2003) Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov 2: 999‐1017 https://www.ncbi.nlm.nih.gov/pubmed/14654798?dopt=AbstractPlus
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=446
Overview
Nomenclature as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/23686350?dopt=AbstractPlus]. The Succinate receptor has been identified as being activated by physiological levels of the Kreb's cycle intermediate succinate and other dicarboxylic acids such as maleate in 2004. Since its pairing with its endogenous ligand, the receptor has been the focus of intensive research and its role has been evidenced in various (patho)physiological processes such as regulation of renin production, retinal angiogenesis, inflammation or immune response.
Comments
In humans, there is the possibility of two open‐reading frames (ORFs) for SUCNR1, one giving a protein of 330 amino acids (AA) and the other one 334‐AA. Wittenberger et al. [http://www.ncbi.nlm.nih.gov/pubmed/11273702?dopt=AbstractPlus] noted that the 330‐AA protein was more likely to be expressed given the Kozak sequence surrounding the second ATG. Some databases report SUCNR1 as being 334‐AA long.
Further reading on Succinate receptor
Ariza AC et al. (2012) The succinate receptor as a novel therapeutic target for oxidative and metabolic stress‐related conditions. Front Endocrinol (Lausanne) 3:22 [https://www.ncbi.nlm.nih.gov/pubmed/22649411?dopt=AbstractPlus]
de Castro Fonseca M et al. (2016) GPR91: expanding the frontiers of Krebs cycle intermediates. Cell Commun. Signal 14:3[https://www.ncbi.nlm.nih.gov/pubmed/26759054?dopt=AbstractPlus]
Gilissen J et al. (2016) Insight into SUCNR1 (GPR91) structure and function. Pharmacol. Ther. 159: 56‐65[https://www.ncbi.nlm.nih.gov/pubmed/26808164?dopt=AbstractPlus]
Grimolizzi F et al. (2018) Multiple faces of succinate beyond metabolism in blood. Haematologica 103: 1586‐1592[https://www.ncbi.nlm.nih.gov/pubmed/29954939?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=62
Overview
Tachykinin receptors (provisional nomenclature as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) are activated by the endogenous peptides http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2098 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11517, http://www.uniprot.org/uniprot/P20366) (SP), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2089) (NKA; previously known as substance K, neurokinin α, neuromedin L), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2090 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11521, http://www.uniprot.org/uniprot/Q9UHF0) (NKB; previously known as neurokinin β, neuromedin K), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2091 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11517, http://www.uniprot.org/uniprot/P20366) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3667 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11517) (N‐terminally extended forms of neurokinin A). The neurokinins (A and B) are mammalian members of the tachykinin family, which includes peptides of mammalian and nonmammalian origin containing the consensus sequence: Phe‐x‐Gly‐LeuMet. Marked species differences in in vitro pharmacology exist for all three receptors, in the context of nonpeptide ligands. Antagonists such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3490 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7623 were approved by FDA and EMA, in combination with other antiemetic agents, for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.
Comments
The NK1 receptor has also been described to couple to G proteins other than Gq/11 [http://www.ncbi.nlm.nih.gov/pubmed/9654151?dopt=AbstractPlus]. The crystal structure of the human NK1 receptor in complex with antagonists has been determined [http://www.ncbi.nlm.nih.gov/pubmed/30604743?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/30538204?dopt=AbstractPlus]. The hexapeptide agonist septide appears to bind to an overlapping but non‐identical site to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2098 (https://www.genenames.org/data/gene‐symbol‐report/%23!/hgnc_id/HGNC:11517, http://www.uniprot.org/uniprot/P20366) on the NK1 receptor. There are additional subtypes of tachykinin receptor;an orphan receptor (Swis‐sProt http://www.ncbi.nlm.nih.gov/protein/266702/) with structural similarities to the NK3 receptor was found to respond to NKB when expressed in Xenopus oocytes or Chinese hamster ovary cells [http://www.ncbi.nlm.nih.gov/pubmed/8947459?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/8990205?dopt=AbstractPlus].
Further reading on Tachykinin receptors
Douglas SD et al. (2011) Neurokinin‐1 receptor: functional significance in the immune system in reference to selected infections and inflammation. Ann. N. Y. Acad. Sci. 1217: 83‐95[https://www.ncbi.nlm.nih.gov/pubmed/21091716?dopt=AbstractPlus]
Foord SM et al. (2005) International Union of Pharmacology. XLVI. G protein‐coupled receptor list. Pharmacol Rev 57: 279‐288[https://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]
Jones S et al. (2008) The neurokinin 1 receptor: a potential new target for anti‐platelet therapy? Curr Opin Pharmacol 8: 114‐9[https://www.ncbi.nlm.nih.gov/pubmed/18296119?dopt=AbstractPlus]
Steinhoff MS et al. (2014) Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol. Rev. 94: 265‐301[https://www.ncbi.nlm.nih.gov/pubmed/24382888?dopt=AbstractPlus]
Yin J et al. (2018) Crystal structure of the human NK_1 tachykinin receptor. Proc. Natl. Acad. Sci. U.S.A. 115: 13264‐13269[https://www.ncbi.nlm.nih.gov/pubmed/30538204?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=63
Overview
Thyrotropin‐releasing hormone (TRH) receptors (provisional nomenclature as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) are activated by the endogenous tripeptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2139 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12298, http://www.uniprot.org/uniprot/P20396) (pGlu‐His‐ProNH2). http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2139 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12298, http://www.uniprot.org/uniprot/P20396) and TRH analogues fail to distinguish TRH1 and TRH2 receptors [http://www.ncbi.nlm.nih.gov/pubmed/12683933?dopt=AbstractPlus]. [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3836) is able to label both TRH1 and TRH2 receptors with Kd values of 13 and 9 nM respectively. Synthesis and biology of ring‐modified L‐Histidine containing TRH analogues has been reported [http://www.ncbi.nlm.nih.gov/pubmed/26854379?dopt=AbstractPlus].
Further reading on Thyrotropin‐releasing hormone receptors
Bílek R etal. (2011) TRH‐like peptides. Physiol Res 60: 207‐15[https://www.ncbi.nlm.nih.gov/pubmed/21114375?dopt=AbstractPlus]
Foord SM et al. (2005) International Union of Pharmacology. XLVI. G protein‐coupled receptor list. Pharmacol Rev 57: 279‐288[https://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]
Nillni EA. (2010) Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs. Front Neuroendocrinol 31: 134‐56[https://www.ncbi.nlm.nih.gov/pubmed/20074584?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=64
Overview
Trace amine‐associated receptors were discovered from a search for novel 5‐HT receptors [http://www.ncbi.nlm.nih.gov/pubmed/11459929?dopt=AbstractPlus], where 15 mammalian orthologues were identified and divided into two families. The TA1 receptor (nomenclature as agreed by the NC‐IUPHAR Subcommittee for the Trace amine receptor [http://www.ncbi.nlm.nih.gov/pubmed/19325074?dopt=AbstractPlus]) has affinity for the endogenous trace amines http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2150, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2144 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2149 in addition to the classical amine http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=940 [http://www.ncbi.nlm.nih.gov/pubmed/11459929?dopt=AbstractPlus]. Emerging evidence suggests that TA1 is a modulator of monoaminergic activity in the brain [http://www.ncbi.nlm.nih.gov/pubmed/19482011?dopt=AbstractPlus] with TA1 and dopamine D2 receptors shown to form constitutive heterodimers when co‐expressed [http://www.ncbi.nlm.nih.gov/pubmed/21670104?dopt=AbstractPlus]. In addition to trace amines, receptors can be activated by amphetamine‐like psychostimulants, and endogenous thyronamines.
Comments
In addition to TA1, in man there are up to 5 functional TAAR genes (TAAR2,5,6,8,9). See [http://www.ncbi.nlm.nih.gov/pubmed/11459929?dopt=AbstractPlus] for detailed discussion. The product of the gene TAAR2 (also known as GPR58) appears to respond to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2144 > http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2150 and to couple through Gs [http://www.ncbi.nlm.nih.gov/pubmed/11459929?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=115#show_object_168, in some individuals, and http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=115#show_object_169 are pseudogenes in man, although functional in rodents. The signalling characteristics and pharmacology of http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=115#show_object_170 (PNR, Putative Neurotransmitter Receptor: https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30236, http://www.uniprot.org/uniprot/O14804), http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=115#show_object_171 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=115#show_object_171 (Trace amine receptor 4, TaR‐4: https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:20978, http://www.uniprot.org/uniprot/96RI8), http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=115#show_object_172 (Trace amine receptor 5, GPR102: https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:14964, http://www.uniprot.org/uniprot/Q969N4) and http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=115#show_object_173 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=115#show_object_173 (trace amine associated receptor 9: https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:20977, http://www.uniprot.org/uniprot/96RI9) are lacking. The thyronamines, endogenous derivatives of thyroid hormone, have affinity for rodent cloned trace amine receptors, including TA1 [http://www.ncbi.nlm.nih.gov/pubmed/15146179?dopt=AbstractPlus]. An antagonist http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5457 has recently been described with a pKi of 9.1 at the mouse TA1 but >5.3 for human TA1 [http://www.ncbi.nlm.nih.gov/pubmed/21237643?dopt=AbstractPlus].
Further reading on Trace amine receptor
Maguire JJ et al. (2009) International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature. Pharmacol. Rev. 61: 1‐8 [https://www.ncbi.nlm.nih.gov/pubmed/19325074?dopt=AbstractPlus]
Pei Y et al. (2016) Trace Amines and the Trace Amine‐Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications. Front Neurosci 10: 148 [https://www.ncbi.nlm.nih.gov/pubmed/27092049?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=65
Overview
The urotensin‐II (U‐II) receptor (UT, nomenclature as agreed by the NC‐IUPHAR Subcommittee on the Urotensin receptor [516, http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25535277?dopt=AbstractPlus]) is activated by the endogenous dodecapeptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2153 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12636, http://www.uniprot.org/uniprot/O95399), originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [http://www.ncbi.nlm.nih.gov/pubmed/2864726?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20633133?dopt=AbstractPlus]. Several structural forms of U‐II exist in fish and amphibians. The goby orthologue was used to identify U‐II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 [http://www.ncbi.nlm.nih.gov/pubmed/9861051?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10581185?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10548501?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10559967?dopt=AbstractPlus]. Human http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2153), an 11‐amino‐acid peptide [http://www.ncbi.nlm.nih.gov/pubmed/9861051?dopt=AbstractPlus], retains the cyclohexapeptide sequence of goby U‐II that is thought to beimportant in ligand binding [http://www.ncbi.nlm.nih.gov/pubmed/12807997?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12203418?dopt=AbstractPlus]. This sequence is also conserved in the deduced amino‐acid sequence of rat http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2155 {Rat} (14 amino‐acids) and mouse http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2154 {Mouse} (14 amino‐acids), although the N‐terminal is more divergent from the human sequence [http://www.ncbi.nlm.nih.gov/pubmed/10486557?dopt=AbstractPlus]. A second endogenous ligand for the UT has been discovered in rat [http://www.ncbi.nlm.nih.gov/pubmed/17628210?dopt=AbstractPlus]. This is the http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2156 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30894, http://www.uniprot.org/uniprot/Q765I0), an octapeptide that is derived from a different gene, but shares the C‐terminal sequence (CFWKYCV) common to U‐II from other species. Identical sequences to rat http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2156) are predicted for the mature mouse and human peptides [http://www.ncbi.nlm.nih.gov/pubmed/18710417?dopt=AbstractPlus]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [http://www.ncbi.nlm.nih.gov/pubmed/25535277?dopt=AbstractPlus].
Comments
In the human vasculature, human http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2153 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12636, http://www.uniprot.org/uniprot/O95399) elicits both vasoconstrictor (pD 2 9.3‐10.1, [http://www.ncbi.nlm.nih.gov/pubmed/11015293?dopt=AbstractPlus]) and vasodilator (pIC50 10.3‐10.4, [http://www.ncbi.nlm.nih.gov/pubmed/11158995?dopt=AbstractPlus]) responses.
Further reading on Urotensin receptor
Foord SM et al. (2005) International Union of Pharmacology. XLVI. G protein‐coupled receptor list. Pharmacol Rev 57: 279‐288[https://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]
Hunt BD et al. (2010) A rat brain atlas of urotensin‐II receptor expression and a review of central urotensin‐II effects. Naunyn Schmiedebergs Arch. Pharmacol. 382:1‐31[https://www.ncbi.nlm.nih.gov/pubmed/20422157?dopt=AbstractPlus]
Maryanoff BE et al. (2010) Urotensin‐II receptor modulators as potential drugs. J. Med. Chem. 53: 2695‐708[https://www.ncbi.nlm.nih.gov/pubmed/20043680?dopt=AbstractPlus]
Ross B et al. (2010) Role of urotensin II in health and disease. Am.J.Physiol.Regul.Integr.Comp. Physiol. 298: R1156‐72[https://www.ncbi.nlm.nih.gov/pubmed/20421634?dopt=AbstractPlus]
Vaudry H et al. (2015) International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, urotensin II‐related peptide, and their receptor: from structure to function. Pharmacol. Rev. 67: 214‐58[https://www.ncbi.nlm.nih.gov/pubmed/25535277?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=66
Overview
Vasopressin (AVP) and oxytocin (OT) receptors (nomenclature as recommended by NC‐IUPHAR [http://www.ncbi.nlm.nih.gov/pubmed/15914470?dopt=AbstractPlus]) are activated by the endogenous cyclic nonapeptides http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2168 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:894, http://www.uniprot.org/uniprot/P01185) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2174 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8528, http://www.uniprot.org/uniprot/P01178). These peptides are derived from precursors which also produce neurophysins (neurophysin I for oxytocin; neurophysin II for vasopressin). Vasopressin and oxytocin differ at only 2 amino acids (positions 3 and 8). There are metabolites of these neuropeptides that may be biologically active [http://www.ncbi.nlm.nih.gov/pubmed/8258377?dopt=AbstractPlus].
Comments
Vasopressin and oxytocin receptors have a characteristic and sometimes overlapping distribution in a number of tissues including brain. There are phylogenetic, ontogenetic and sex‐specific differences in the levels and distribution of these receptors, particularly in the brain. The V2 receptor exhibits marked species differences, such that many ligands (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2236 and [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3817) exhibit low affinity at human V2 receptors [http://www.ncbi.nlm.nih.gov/pubmed/9773787?dopt=AbstractPlus]. Similarly, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2170 is more V2 selective in the rat than in the human [http://www.ncbi.nlm.nih.gov/pubmed/9264324?dopt=AbstractPlus]. The gene encoding the V2 receptor is polymorphic in man, underlying nephrogenic diabetes insipidus [http://www.ncbi.nlm.nih.gov/pubmed/9756088?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2187 is selective only for the human and bovine V1B receptors [http://www.ncbi.nlm.nih.gov/pubmed/12446593?dopt=AbstractPlus], while http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2191 has high affinity for the rat V1B receptor [http://www.ncbi.nlm.nih.gov/pubmed/17300166?dopt=AbstractPlus]. Knockouts of vasopressin and oxytocin receptors have systemspecific defects (e.g., impaired ability toconcentrate urine in V2 receptor knockouts) which include behavioural deficits (principally in V1A, V 1B and OT receptor knockouts).
Further reading on Vasopressin and oxytocin receptors
Knepper MA. (2012) Systems biology in physiology: the vasopressin signaling network in kidney. Am. J. Physiol., Cell Physiol. 303: C1115‐24[https://www.ncbi.nlm.nih.gov/pubmed/22932685?dopt=AbstractPlus]
Koshimizu TA et al. (2012) Vasopressin V1a and V1b receptors: from molecules to physiological systems. Physiol. Rev. 92: 1813‐64[https://www.ncbi.nlm.nih.gov/pubmed/23073632?dopt=AbstractPlus]
Manning M et al. (2012) Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics. J. Neuroendocrinol. 24: 609‐28[https://www.ncbi.nlm.nih.gov/pubmed/22375852?dopt=AbstractPlus]
Meyer‐Lindenberg A et al. (2011) Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat. Rev. Neurosci. 12: 524‐38[https://www.ncbi.nlm.nih.gov/pubmed/21852800?dopt=AbstractPlus]
Neumann ID et al. (2012) Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci. 35: 649‐59[https://www.ncbi.nlm.nih.gov/pubmed/22974560?dopt=AbstractPlus]
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=67
Overview
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase‐activating peptide (PACAP) receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [http://www.ncbi.nlm.nih.gov/pubmed/9647867?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/22289055?dopt=AbstractPlus]) are activated by the endogenous peptides http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1152 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12693, http://www.uniprot.org/uniprot/P01282), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2258 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:241, http://www.uniprot.org/uniprot/P18509), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2257), peptide histidine isoleucineamide (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4397 {Mouse, Rat}), peptide histidine methionineamide (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2274)) and peptide histidine valine (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3706)). VPAC1 and VPAC2 receptors display comparable affinity for the PACAP peptides, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2257) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2258), and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1152 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12693, http://www.uniprot.org/uniprot/P01282), whereas http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2257 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:241, http://www.uniprot.org/uniprot/P18509) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2258) are >100 fold more potent than http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1152) as agonists of most isoforms of the PAC1 receptor. However, one splice variant of the human PAC1 receptor has been reported to respond to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2258), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2257) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1152) with comparable affinity [http://www.ncbi.nlm.nih.gov/pubmed/10583729?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2272 [http://www.ncbi.nlm.nih.gov/pubmed/11068102?dopt=AbstractPlus] has been used as a selective VPAC2 receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC1 and PAC1 receptors [http://www.ncbi.nlm.nih.gov/pubmed/16930633?dopt=AbstractPlus]. The selective PAC1 receptor agonist http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2264, was extracted from the salivary glands of sand flies (Lutzomyia longipalpis) and has no sequence homology to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1152) or the PACAP peptides [http://www.ncbi.nlm.nih.gov/pubmed/8995389?dopt=AbstractPlus]. Two deletion variants of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2264, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3305 [http://www.ncbi.nlm.nih.gov/pubmed/9928019?dopt=AbstractPlus] and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2265 [http://www.ncbi.nlm.nih.gov/pubmed/10438479?dopt=AbstractPlus] have been reported to be PAC1 receptor antagonists, but these peptides have not been extensively characterised.
Comments
Subtypes of PAC1 receptors have been proposed based on tissue differences in the potencies of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2257 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:241, http://www.uniprot.org/uniprot/P18509) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2258); these might result from differences in G protein coupling and second messenger mechanisms [http://www.ncbi.nlm.nih.gov/pubmed/8967982?dopt=AbstractPlus], or from alternative splicing of PAC1 receptor mRNA [http://www.ncbi.nlm.nih.gov/pubmed/8396727?dopt=AbstractPlus].
Further reading on VIP and PACAP receptors
Harmar AJ et al. (1998) International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase‐activating polypeptide. Pharmacol Rev 50: 265‐270[https://www.ncbi.nlm.nih.gov/pubmed/9647867?dopt=AbstractPlus]
Harmar AJ et al. (2012) Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase‐activating polypeptide: IUPHAR review 1. Br. J. Pharmacol. 166: 4‐17[https://www.ncbi.nlm.nih.gov/pubmed/22289055?dopt=AbstractPlus]
Reglodi D et al. (2012) Effects of pituitary adenylate cyclase activating polypeptide in the urinary system, with special emphasis on its protective effects in the kidney. Neuropeptides 46: 61‐70[https://www.ncbi.nlm.nih.gov/pubmed/21621841?dopt=AbstractPlus]
Smith CB et al. (2012) Is PACAP the major neurotransmitter for stress transduction at the adrenomedullary synapse? J. Mol. Neurosci. 48: 403‐12[https://www.ncbi.nlm.nih.gov/pubmed/22610912?dopt=AbstractPlus]
Alexander Stephen PH, Christopoulos Arthur, Davenport Anthony P, Kelly Eamonn, Mathie Alistair, Peters John A, Veale Emma L, Armstrong Jane F, Faccenda Elena, Harding Simon D, Pawson Adam J, Sharman Joanna L, Southan Christopher, Davies Jamie A and CGTP Collaborators (2019) THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology, 176: S21–S141. doi: 10.1111/bph.14748.
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