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Review
. 2015 Apr 15:6:69.
doi: 10.3389/fphar.2015.00069. eCollection 2015.

The therapeutic potential of orphan GPCRs, GPR35 and GPR55

Derek M Shore  1 , Patricia H Reggio  1
Affiliations
Review

The therapeutic potential of orphan GPCRs, GPR35 and GPR55

Derek M Shore et al. Front Pharmacol. .

Abstract

The G protein-coupled receptor (GPCR) superfamily of integral proteins is the largest family of signal transducers, comprised of ∼1000 members. Considering their prevalence and functional importance, it's not surprising that ∼60% of drugs target GPCRs. Regardless, there exists a subset of the GPCR superfamily that is largely uncharacterized and poorly understood; specifically, more than 140 GPCRs have unknown endogenous ligands-the so-called orphan GPCRs. Orphan GPCRs offer tremendous promise, as they may provide novel therapeutic targets that may be more selective than currently known receptors, resulting in the potential reduction in side effects. In addition, they may provide access to signal transduction pathways currently unknown, allowing for new strategies in drug design. Regardless, orphan GPCRs are an important area of inquiry, as they represent a large gap in our understanding of signal transduction at the cellular level. Here, we focus on the therapeutic potential of two recently deorphanized GPCRs: GPR35/CXCR8 and GPR55. First, GPR35/CXCR8 has been observed in numerous tissues/organ systems, including the gastrointestinal tract, liver, immune system, central nervous system, and cardiovascular system. Not surprisingly, GPR35/CXCR8 has been implicated in numerous pathologies involving these tissues/systems. While several endogenous ligands have been identified, GPR35/CXCR8 has recently been observed to bind the chemokine CXCL17. Second, GPR55 has been observed to be expressed in the central nervous system, adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder, kidney, and bone, as well as, other tissues/organ systems. Likewise, it is not surprising that GPR55 has been implicated in pathologies involving these tissues/systems. GPR55 was initially deorphanized as a cannabinoid receptor and this receptor does bind many cannabinoid compounds. However, the GPR55 endogenous ligand has been found to be a non-cannabinoid, lysophophatidylinositol (LPI) and subsequent high throughput assays have identified other GPR55 ligands that are not cannabinoids and do not bind to either the cannabinoid CB1 and CB2 receptors. Here, we review reports that suggest that GPR35/CXCR8 and GPR55 may be promising therapeutic targets, with diverse physiological roles.

Keywords: 2-oleoyl LPA; CXCR8; GPR35; GPR55; LPI; kynurenic acid.

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Figures

FIGURE 1
FIGURE 1
Helix net representation of human GPR35/CXCR8 receptor structure. The most highly conserved residue in each transmembrane helix (among Class A GPCRs) is shown in red. Possible disulfide bridges are indicated by double-headed arrows.
FIGURE 2
FIGURE 2
Synthetic GPR35/CXCR8 agonists and antagonists. These compounds are among the best characterized synthetic compounds at GPR35.
FIGURE 3
FIGURE 3
Compounds that are used (or have the potential) to treat asthma/inflammation. Cromoyln (4) and Nedocromil (7) are used in the treatment of asthma/inflammatory states. Gallic acid (6) and wedelolactone (8) have been reported to be potential anti-asthma/anti-inflammatory compounds. DHNA (5) has been suggested that it may be useful in the treatment of bowel inflammation.
FIGURE 4
FIGURE 4
Compounds that have been reported to be endogenous agonists of GPR35/CXCR8.
FIGURE 5
FIGURE 5
Homology models of pamoic acid and zaprinast docked at WT and R6.58(240)A. The view is from the lipid bilayer, toward TMH3-4; pamoic acid is shown in blue; zaprinast is shown in orange; residues that form a salt bridge/π interactions are shown in lavender; residues that form hydrogen bonds are shown in yellow; residues that form van der Waals interactions are shown in pink. (A) Pamoic acid docked in the human WT GPR35/CXCR8 model; (B) Pamoic acid docked in the human R6.58(240)A GPR35/CXCR8 model; (C) Zaprinast docked in the human WT GPR35/CXCR8 model; (D) Zaprinast docked in the human R6.58(240)A GPR35/CXCR8 model.
FIGURE 6
FIGURE 6
A helix net representation for GPR55 is provided here.
FIGURE 7
FIGURE 7
Cannabinoid agonists that activate GPR55 are shown here.
FIGURE 8
FIGURE 8
Cannabinoid antagonists that inhibit GPR55 signaling are shown here.
FIGURE 9
FIGURE 9
Non-Cannabinoid agonists that activate GPR55 are shown here. *CID1135734 (34), while structurally related to other GPR55 agonists, does not bind to GPR55 and was used as a negative control.
FIGURE 10
FIGURE 10
Non-Cannabinoid antagonists that inhibit GPR55 signaling are shown here.
FIGURE 11
FIGURE 11
Homology models of CID1792197 (30; agonist) and ML191 (35; antagonist) docked at WT R* (active) and R (inactive) GPR55 models, respectively. The view is from the lipid bilayer, toward TMH6-7; residues that form the ‘toggle switch’ are shown in lavender; residues that form hydrogen bonds are shown in yellow; residues that form van der Waals interactions are shown in orange; hydrogen bonds are shown as dashed yellow lines. (A) CID1792197 (agonist, blue) in the human WT GPR55 R* model; (B) ML191 (antagonist, pink) in the human GPR55 R model. Notice that ML191 is docked more extracellularly than CID1792197 and sterically blocks the toggle switch residues (lavender) from undergoing necessary conformational changes via interactions with F6.55 (i.e., ML191 packs against F6.55, which in turn packs against M3.36).
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References

    1. Abed E., Labelle D., Martineau C., Loghin A., Moreau R. (2009). Expression of transient receptor potential (TRP) channels in human and murine osteoblast-like cells. Mol. Membr. Biol. 26 146–158 10.1080/09687680802612721 - DOI - PubMed
    1. Alkondon M., Pereira E. F., Todd S. W., Randall W. R., Lane M., Albuquerque E. X. (2014). Functional G-protein coupled receptor 35 is expressed by neurons in the CA1 field of the hippocampus. Biochem. Pharmacol. 93 506–518 10.1016/j.bcp.2014.12.009 - DOI - PubMed
    1. Andradas C., Caffarel M. M., Perez-Gomez E., Salazar M., Lorente M., Velasco G., et al. (2011). The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK. Oncogene 30 245–252 10.1038/onc.2010.402 - DOI - PubMed
    1. Arad Y., Spadaro L. A., Goodman K., Newstein D., Guerci A. D. (2000). Prediction of coronary events with electron beam computed tomography. J. Am. Coll. Cardiol. 36 1253–1260 10.1016/S0735-1097(00)00872-X - DOI - PubMed
    1. Barth M. C., Ahluwalia N., Anderson T. J., Hardy G. J., Sinha S., Alvarez-Cardona J. A., et al. (2009). Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions. J. Biol. Chem. 284 19189–19195 10.1074/jbc.M109.024042 - DOI - PMC - PubMed

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