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Review
. 2021 Feb;178(3):489-514.
doi: 10.1111/bph.15299. Epub 2020 Dec 21.

Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

Peter Illes  1   2 , Christa E Müller  3 , Kenneth A Jacobson  4 , Thomas Grutter  5 , Annette Nicke  6 , Samuel J Fountain  7 , Charles Kennedy  8 , Günther Schmalzing  9 , Michael F Jarvis  10 , Stanko S Stojilkovic  11 , Brian F King  12 , Francesco Di Virgilio  13
Affiliations
Review

Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

Peter Illes et al. Br J Pharmacol. 2021 Feb.

Abstract

The known seven mammalian receptor subunits (P2X1-7) form cationic channels gated by ATP. Three subunits compose a receptor channel. Each subunit is a polypeptide consisting of two transmembrane regions (TM1 and TM2), intracellular N- and C-termini, and a bulky extracellular loop. Crystallization allowed the identification of the 3D structure and gating cycle of P2X receptors. The agonist-binding pocket is located at the intersection of two neighbouring subunits. In addition to the mammalian P2X receptors, their primitive ligand-gated counterparts with little structural similarity have also been cloned. Selective agonists for P2X receptor subtypes are not available, but medicinal chemistry supplied a range of subtype-selective antagonists, as well as positive and negative allosteric modulators. Knockout mice and selective antagonists helped to identify pathological functions due to defective P2X receptors, such as male infertility (P2X1), hearing loss (P2X2), pain/cough (P2X3), neuropathic pain (P2X4), inflammatory bone loss (P2X5), and faulty immune reactions (P2X7).

Keywords: (patho)physiological functions; P2X receptors; agonists; antagonists; extracellular ATP; knockout mice; ligand-gated cationic channels.

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Conflict of interest statement

CONFLICT OF INTEREST

F.D.V. is a member of the Scientific Advisory Board of Biosceptre Ltd, a UK-based biotech company involved in the development of P2X7-targeted therapeutic antibodies. The other authors declare no competing interest.

Figures

FIGURE 1
FIGURE 1
Selected P2X receptor agonists, nucleotide-derived antagonists, and positive allosteric modulators
FIGURE 2
FIGURE 2
P2X receptor subtype-selective antagonists
FIGURE 3
FIGURE 3
Structures of selected P2X receptors. (a) Structure of the hP2X3 receptor bound to ATP (PBD ID: 5SVK) (Mansoor et al., 2016). The hP2X3 receptor is shown in blue cartoon representation, and ATP is shown as spheres (carbon is yellow, oxygen is red, nitrogen is blue, and phosphorus is orange). Horizontal grey bars indicate the approximate location of the membrane bilayer defining the extracellular (out) and intracellular (in) milieu. (b) Structure of zfP2X4 receptor bound to ATP (4DW1) (Hattori & Gouaux, 2012). The zfP2X4 receptor is shown in green cartoon representation, and ATP is shown as spheres. (c) Structure of the rP2X7 receptor bound to ATP (6U9W) (McCarthy, Yoshioka, & Mansoor, 2019). The rP2X7 receptor is shown in cyan cartoon representation, and ATP is shown as spheres. (d) Structure of the invertebrate AmP2X receptor bound to ATP (5F1C) (Kasuya et al., 2016). The AmP2X receptor is shown in orange cartoon representation, and ATP is shown as spheres. Note the structural similarity between vertebrate and invertebrate P2X receptors. For structures having undergone heavy truncations, membrane spanning helices are lacking in their intracellular sides. (e–g) Close-up views of ATP-binding sites from hP2X3 receptors (e), zfP2X4 receptors (f), and rP2X7 receptors (g). For comparison, views are taken from similar angles, and displayed residues are equivalent across P2X receptors, except for S275 and K193. For those not directly contributing to ATP binding (distance >3.5 Å), equivalent residues are not displayed (e.g., K64 in rP2X7 receptors). ATP is shown in stick representation (carbon is yellow, oxygen red, nitrogen blue, and phosphorus orange) with positions of α-, β-, and γ-phosphate. The oxygen atom from a glycerol molecule (GOL) is shown in sphere representation. Black dashed lines indicate hydrogen bonding (<3.5 Å). AmP2XR, Gulf Coast tick Amblyomma maculatum P2X receptor; hP2X3R, human P2X3 receptor; rP2X7R, rat P2X7 receptor; zfP2X4R, zebrafish P2X4 receptor
FIGURE 4
FIGURE 4
Currently available P2X receptor mouse models according to the literature and Mouse Genome Informatics (MGI)/International Mouse Strain Resource (IMSR). (a) Strategies to target P2rx1–P2rx7 genes for the generation of knockout, knock-in, and transgenic mouse models. The nomenclature according to the current guidelines of the International Committee on Standardized Genetic Nomenclature for Mice is summarized in the inset and found on the mouse nomenclature home page (http://www.informatics.jax.org/mgihome/nomen/index.shtml). P2rx4mCherryIN is not named accordingly, yet. Light yellow boxes represent exons, and black and coloured boxes represent introduced reporter/selection cassettes and/or cDNA. Circles behind the names indicate alleles that are only available in ES cells. In case of conditional strategies, only tm1a alleles (“ko-first”) are shown. These can be further modified as described in (b). Further knockout strains are available from Taconic (deleted exons in brackets) for P2rx1 (2–7), P2rx4 (2–4), P2rx5 (1), P2rx6 (1–2), and P2rx7 (2–3) and from TIGM (gene trap vector insertion in brackets) for P2rx1 (IST14381H9), (IST12457B12), and P2rx3 (IST10786C2). In addition, P2rx2em1(IMPC)H, P2rx4Gt(OST340739)Lex, and Gt (ROSA)26Sortm10(RNAi:P2rx7)Rkuhn are available. Targeted reporter-tagged insertion with conditional (b) potential (ko-first, conditional ready) and reporter-tagged deletion alleles (c) and the respective nomenclature. Derivative alleles can be obtained through recombinase (Flp or Cre, as indicated)-mediated changes (https://mpi2.github.io/IKMC-knowledgebase/2010/08/24/what-are-the-allele-types.html). The lacZ reporter is supposed to be spliced to the upstream exon 1 (a). However, skipping of lacZ (b) and splicing to the downstream (critical) exon (resulting in functional WT or hypomorph) cannot be excluded and needs to be experimentally determined. The critical exon is supposed to produce a frameshift mutation upon deletion. Note that tm1e represents an unplanned by-product of the original targeting strategy in which the 3′loxP site was lost during recombination but which might still be useful. For detailed information and references, see Kaczmarek-Hajek, Lörinczi, Hausmann, and Nicke (2012), Nicke, Grutter, and Egan (2018), http://www.informatics.jax.org/, and http://www.findmice.org/
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