P2X receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2X Receptors [6,36]) have a trimeric topology [25,31,35,54] with two putative TM domains per P2X subunit, gating primarily Na⁺, K⁺ and Ca²⁺, exceptionally Cl^-. The Nomenclature Subcommittee has recommended that for P2X receptors, structural criteria should be the initial basis for nomenclature where possible. X-ray crystallography indicates that functional P2X receptors are trimeric and three agonist molecules are required to bind to a single trimeric assembly in order to activate it [20-21,25,35,44]. Native receptors may occur as either homotrimers (e.g. P2X1 in smooth muscle) or heterotrimers (e.g. P2X2:P2X3 in the nodose ganglion [73], P2X1:P2X5 in mouse cortical astrocytes [42], and P2X2:P2X5 in mouse dorsal root ganglion, spinal cord and mid pons [7,64]. P2X2, P2X4 and P2X7 receptor activation can lead to influx of large cationic molecules, such as NMDG⁺, Yo-Pro, ethidium or propidium iodide [61]. The permeability of the P2X7 receptor is modulated by the amount of cholesterol in the plasma membrane [53]. The hemi-channel pannexin-1 was initially implicated in the action of P2X7 [60], but not P2X2, receptors [5], but this interpretation is probably misleading [62]. Convincing evidence now supports the view that the activated P2X7 receptor is immediately permeable to large cationic molecules, but influx proceeds at a much slower pace than that of the small cations Na⁺, K⁺, and Ca²⁺ [11].

A317491 and RO3 also block the P2X2:P2X3 heteromultimer [17,30]. NF449, A317491 and RO3 are more than 10-fold selective for P2X1 and P2X3 receptors, respectively.

Agonists listed show selectivity within recombinant P2X receptors of ca. one order of magnitude. A804598, A839977, A740003 and A438079 are at least 10-fold selective for P2X7 receptors and show similar affinity across human and rodent receptors [12,14,23].

Several P2X receptors (particularly P2X1 and P2X3) may be inhibited by desensitisation using stable agonists (e.g. αΒ-meATP); suramin and PPADS are non-selective antagonists at rat and human P2X1-3,5 and hP2X4, but not rP2X4,6,7 [4], and can also inhibit ATPase activity [8]. Ip₅I is inactive at rP2X2, an antagonist at rP2X3 (pIC₅₀ 5.6) and enhances agonist responses at rP2X4 [39]. Antagonist potency of NF023 at recombinant P2X2, P2X3 and P2X5 is two orders of magnitude lower than that at P2X1 receptors [68]. The P2X7 receptor may be inhibited in a non-competitive manner by the protein kinase inhibitors KN62 and chelerythrine [67], while the p38 MAP kinase inhibitor GTPγS and the cyclic imide AZ11645373 show a species-dependent non-competitive action [13,50-51,69]. The pH-sensitive dye used in culture media, phenol red, is also reported to inhibit P2X1 and P2X3 containing channels [40]. Some recombinant P2X receptors expressed to high density bind [³⁵S]ATPγS and [³H]αβ-meATP, although the latter can also bind to 5′-nucleotidase [48]. [³H]A317491 and [³H]A804598 have been used as high affinity antagonist radioligands for P2X3 (and P2X2/3) and P2X7 receptors, respectively [14]. Several high affinity radioligands for the P2X7 receptor have been recently synthesized, some with very promising applications in the diagnosis of inflammatory diseases of the central nervous system [15,43,66,70,75]. Several P2X3 antagonists have entered clinical trials for refractory chronic cough. In 2022, gefapixant was approved in Japan for the management of refractory or unexplained chronic cough [45]. Oxidized ATP covalently binds un-protonated lysine residues in the vicinity of the ATP-binding site and irreversibly inhibits the P2X7 receptor. Other plasma membrane receptors exposing available lysines may also be blocked by oATP [2,10]. The cryoelectron microscopy structures of full-length rP2X7 receptor in apo and ATP-bound states have been resolved [46]. A proportion (<10%) of screened humans were found to possess full length P2X5 subunits (444 aa), which can assemble into a functional P2X5 receptor [38,41]. An uncharged region at the N-terminus of P2X6 exerts an inhibitory effect on its assembly and export from the ER [59]. The P2X6 subunit also lacks nine residues in the left flipper, which is a key element in agonist docking at P2X receptors [58].

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Subcommittee members: Charles Kennedy (Chairperson) Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde 161 Cathedral Street Glasgow, G4 0RE UK Francesco Di Virgilio Department of Medical Sciences University of Ferrara Via Borsari 46 44121, Ferrara Italy Samuel J. Fountain Biomedical Research Centre School of Biological Sciences University of East Anglia Norwich UK Michael F. Jarvis Dept of Pharmaceutical Sciences University of Illinois-Chicago 833 South Wood Street Chicago Illinois 60612 USA Brian F. King Department of Neuroscience, Physiology & Pharmacology University College London, London WC1E 6BT United Kingdom Annette Nicke Ludwig-Maximilians-Universität München Walther Straub Institute of Pharmacology and Toxicology Nußbaumstr. 26 80336 Munich Germany

Other contributors: Simonetta Falzoni Department of Medical Sciences University of Ferrara Via Borsari 46 44121, Ferrara Italy Anna Fortuny-Gomez Biomedical Research Centre School of Biological Sciences University of East Anglia Norwich UK Jessica Meades Biomedical Research Centre School of Biological Sciences University of East Anglia Norwich UK John A. Peters Room CB 08 Carnelley Building School of Life Sciences The University of Dundee Dundee DD1 5EH Scotland UK