More information on this family may be found on the IUPHAR-DB family and introduction pages.
P2X receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on P2X Receptors, [3,17]) are ligand-gated ion channels with a trimeric topology [13,16,25], gating primarily Na+, K+ and Ca2+, exceptionally Cl- with two putative TM domains, where the endogenous ligand is ATP. The Nomenclature Subcommittee has recommended that for P2X receptors, structural criteria should be the initial criteria for nomenclature where possible. The P2X receptor nomenclature recommended below reflects the newly accepted format for ligand-gated ion channels [3]. Functional P2X receptors exist as polymeric transmitter-gated channels; the native receptors may occur as either homopolymers (e.g. P2X1 in smooth muscle) or heteropolymers (e.g. P2X2:P2X3 in the nodose ganglion and P2X1:P2X5 in mouse cortical astrocytes, [20]). P2X2, P2X4 and P2X7 receptors have been shown to form functional homopolymers which, in turn, activate pores permeable to low molecular weight solutes [30]. The hemi-channel pannexin-1 has been implicated in the pore formation induced by P2X7 [26], but not P2X2 [2], receptor activation.
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Subunits 
|
|||||||||||||||||||||
|
|||||||||||||||||||||
|
|||||||||||||||||||||
|
|||||||||||||||||||||
|
|||||||||||||||||||||
|
|||||||||||||||||||||
|
Browne, LE; Cao, L; Broomhead, HE; Bragg, L; Wilkinson, WJ; North, RA. (2011) P2X receptor channels show threefold symmetry in ionic charge selectivity and unitary conductance. Nat. Neurosci., 14 (1): 17-8. [PMID:21170052]
Browne, LE; Jiang, LH; North, RA. (2010) New structure enlivens interest in P2X receptors. Trends Pharmacol. Sci., 31 (5): 229-37. [PMID:20227116]
Burnstock, G. (2008) Purinergic signalling and disorders of the central nervous system. Nat Rev Drug Discov, 7 (7): 575-90. [PMID:18591979]
Collingridge, GL; Olsen, RW; Peters, J; Spedding, M. (2009) A nomenclature for ligand-gated ion channels. Neuropharmacology, 56 (1): 2-5. [PMID:18655795]
Donnelly-Roberts, D; McGaraughty, S; Shieh, CC; Honore, P; Jarvis, MF. (2008) Painful purinergic receptors. J. Pharmacol. Exp. Ther., 324 (2): 409-15. [PMID:18042830]
Evans, RJ. (2010) Structural interpretation of P2X receptor mutagenesis studies on drug action. Br. J. Pharmacol., 161 (5): 961-71. [PMID:20977449]
Guile, SD; Alcaraz, L; Birkinshaw, TN; Bowers, KC; Ebden, MR; Furber, M; Stocks, MJ. (2009) Antagonists of the P2X(7) receptor. From lead identification to drug development. J. Med. Chem., 52 (10): 3123-41. [PMID:19191585]
Hu, H; Hoylaerts, MF. (2010) The P2X1 ion channel in platelet function. Platelets, 21 (3): 153-66. [PMID:20201633]
Jarvis, MF. (2010) The neural-glial purinergic receptor ensemble in chronic pain states. Trends Neurosci., 33 (1): 48-57. [PMID:19914722]
Jarvis, MF; Khakh, BS. (2009) ATP-gated P2X cation-channels. Neuropharmacology, 56 (1): 208-15. [PMID:18657557]
Khakh, BS; Burnstock, G; Kennedy, C; King, BF; North, RA; Séguéla, P; Voigt, M; Humphrey, PP. (2001) International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits. Pharmacol. Rev., 53 (1): 107-18. [PMID:11171941]
Pankratov, Y; Lalo, U; Krishtal, OA; Verkhratsky, A. (2009) P2X receptors and synaptic plasticity. Neuroscience, 158 (1): 137-48. [PMID:18495357]
Skaper, SD; Debetto, P; Giusti, P. (2010) The P2X7 purinergic receptor: from physiology to neurological disorders. FASEB J., 24 (2): 337-45. [PMID:19812374]
Surprenant, A; North, RA. (2009) Signaling at purinergic P2X receptors. Annu. Rev. Physiol., 71: 333-59. [PMID:18851707]
Young, MT. (2010) P2X receptors: dawn of the post-structure era. Trends Biochem. Sci., 35 (2): 83-90. [PMID:19836961]
Zemková, H; Balík, A; Jindrichová, M; Vávra, V. (2008) Molecular structure of purinergic P2X receptors and their expression in the hypothalamus and pituitary. Physiol Res, 57 Suppl 3: S23-38. [PMID:18481917]
1. Buell, G; Lewis, C; Collo, G; North, RA; Surprenant, A. (1996) An antagonist-insensitive P2X receptor expressed in epithelia and brain. EMBO J., 15 (1): 55-62. [PMID:8598206]
2. Chaumont, S; Khakh, BS. (2008) Patch-clamp coordinated spectroscopy shows P2X2 receptor permeability dynamics require cytosolic domain rearrangements but not Panx-1 channels. Proc. Natl. Acad. Sci. U.S.A., 105 (33): 12063-8. [PMID:18689682]
3. Collingridge, GL; Olsen, RW; Peters, J; Spedding, M. (2009) A nomenclature for ligand-gated ion channels. Neuropharmacology, 56 (1): 2-5. [PMID:18655795]
4. Crack, BE; Beukers, MW; McKechnie, KC; Ijzerman, AP; Leff, P. (1994) Pharmacological analysis of ecto-ATPase inhibition: evidence for combined enzyme inhibition and receptor antagonism in P2X-purinoceptor ligands. Br. J. Pharmacol., 113 (4): 1432-8. [PMID:7889301]
5. Donnelly-Roberts, DL; Jarvis, MF. (2007) Discovery of P2X7 receptor-selective antagonists offers new insights into P2X7 receptor function and indicates a role in chronic pain states. Br. J. Pharmacol., 151 (5): 571-9. [PMID:17471177]
6. Donnelly-Roberts, DL; Namovic, MT; Faltynek, CR; Jarvis, MF. (2004) Mitogen-activated protein kinase and caspase signaling pathways are required for P2X7 receptor (P2X7R)-induced pore formation in human THP-1 cells. J. Pharmacol. Exp. Ther., 308 (3): 1053-61. [PMID:14634045]
7. Donnelly-Roberts, DL; Namovic, MT; Han, P; Jarvis, MF. (2009) Mammalian P2X7 receptor pharmacology: comparison of recombinant mouse, rat and human P2X7 receptors. Br. J. Pharmacol., 157 (7): 1203-14. [PMID:19558545]
8. Ford, AP; Gever, JR; Nunn, PA; Zhong, Y; Cefalu, JS; Dillon, MP; Cockayne, DA. (2006) Purinoceptors as therapeutic targets for lower urinary tract dysfunction. Br. J. Pharmacol., 147 Suppl 2: S132-43. [PMID:16465177]
9. Gargett, CE; Wiley, JS. (1997) The isoquinoline derivative KN-62 a potent antagonist of the P2Z-receptor of human lymphocytes. Br. J. Pharmacol., 120 (8): 1483-90. [PMID:9113369]
10. Gever, JR; Soto, R; Henningsen, RA; Martin, RS; Hackos, DH; Panicker, S; Rubas, W; Oglesby, IB; Dillon, MP; Milla, ME; et al.. (2010) AF-353, a novel, potent and orally bioavailable P2X3/P2X2/3 receptor antagonist. Br. J. Pharmacol., 160 (6): 1387-98. [PMID:20590629]
11. Honore, P; Donnelly-Roberts, D; Namovic, M; Zhong, C; Wade, C; Chandran, P; Zhu, C; Carroll, W; Perez-Medrano, A; Iwakura, Y; et al.. (2009) The antihyperalgesic activity of a selective P2X7 receptor antagonist, A-839977, is lost in IL-1alphabeta knockout mice. Behav. Brain Res., 204 (1): 77-81. [PMID:19464323]
12. Jarvis, MF; Burgard, EC; McGaraughty, S; Honore, P; Lynch, K; Brennan, TJ; Subieta, A; Van Biesen, T; Cartmell, J; Bianchi, B; et al.. (2002) A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc. Natl. Acad. Sci. U.S.A., 99 (26): 17179-84. [PMID:12482951]
13. Jiang, LH; Kim, M; Spelta, V; Bo, X; Surprenant, A; North, RA. (2003) Subunit arrangement in P2X receptors. J. Neurosci., 23 (26): 8903-10. [PMID:14523092]
14. Jiang, LH; Mackenzie, AB; North, RA; Surprenant, A. (2000) Brilliant blue G selectively blocks ATP-gated rat P2X(7) receptors. Mol. Pharmacol., 58 (1): 82-8. [PMID:10860929]
15. Kassack, MU; Braun, K; Ganso, M; Ullmann, H; Nickel, P; Böing, B; Müller, G; Lambrecht, G. (2004) Structure-activity relationships of analogues of NF449 confirm NF449 as the most potent and selective known P2X1 receptor antagonist. Eur J Med Chem, 39 (4): 345-57. [PMID:15072843]
16. Kawate, T; Michel, JC; Birdsong, WT; Gouaux, E. (2009) Crystal structure of the ATP-gated P2X(4) ion channel in the closed state. Nature, 460 (7255): 592-8. [PMID:19641588]
17. Khakh, BS; Burnstock, G; Kennedy, C; King, BF; North, RA; Séguéla, P; Voigt, M; Humphrey, PP. (2001) International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits. Pharmacol. Rev., 53 (1): 107-18. [PMID:11171941]
18. King, BF; Liu, M; Pintor, J; Gualix, J; Miras-Portugal, MT; Burnstock, G. (1999) Diinosine pentaphosphate (IP5I) is a potent antagonist at recombinant rat P2X1 receptors. Br. J. Pharmacol., 128 (5): 981-8. [PMID:10556935]
19. King, BF; Liu, M; Townsend-Nicholson, A; Pfister, J; Padilla, F; Ford, AP; Gever, JR; Oglesby, IB; Schorge, S; Burnstock, G. (2005) Antagonism of ATP responses at P2X receptor subtypes by the pH indicator dye, Phenol red. Br. J. Pharmacol., 145 (3): 313-22. [PMID:15778739]
20. Lalo, U; Pankratov, Y; Wichert, SP; Rossner, MJ; North, RA; Kirchhoff, F; Verkhratsky, A. (2008) P2X1 and P2X5 subunits form the functional P2X receptor in mouse cortical astrocytes. J. Neurosci., 28 (21): 5473-80. [PMID:18495881]
21. Michel, AD; Chau, NM; Fan, TP; Frost, EE; Humphrey, PP. (1995) Evidence that [3H]-alpha,beta-methylene ATP may label an endothelial-derived cell line 5'-nucleotidase with high affinity. Br. J. Pharmacol., 115 (5): 767-74. [PMID:8548175]
22. Michel, AD; Ng, SW; Roman, S; Clay, WC; Dean, DK; Walter, DS. (2009) Mechanism of action of species-selective P2X(7) receptor antagonists. Br. J. Pharmacol., 156 (8): 1312-25. [PMID:19309360]
23. Michel, AD; Thompson, KM; Simon, J; Boyfield, I; Fonfria, E; Humphrey, PP. (2006) Species and response dependent differences in the effects of MAPK inhibitors on P2X(7) receptor function. Br. J. Pharmacol., 149 (7): 948-57. [PMID:17031382]
24. Michel, AD; Xing, M; Thompson, KM; Jones, CA; Humphrey, PP. (2006) Decavanadate, a P2X receptor antagonist, and its use to study ligand interactions with P2X7 receptors. Eur. J. Pharmacol., 534 (1-3): 19-29. [PMID:16487507]
25. Nicke, A; Bäumert, HG; Rettinger, J; Eichele, A; Lambrecht, G; Mutschler, E; Schmalzing, G. (1998) P2X1 and P2X3 receptors form stable trimers: a novel structural motif of ligand-gated ion channels. EMBO J., 17 (11): 3016-28. [PMID:9606184]
26. Pelegrin, P; Surprenant, A. (2009) The P2X(7) receptor-pannexin connection to dye uptake and IL-1beta release. Purinergic Signal., 5 (2): 129-37. [PMID:19212823]
27. Shemon, AN; Sluyter, R; Conigrave, AD; Wiley, JS. (2004) Chelerythrine and other benzophenanthridine alkaloids block the human P2X7 receptor. Br. J. Pharmacol., 142 (6): 1015-9. [PMID:15210579]
28. Soto, F; Lambrecht, G; Nickel, P; Stühmer, W; Busch, AE. (1999) Antagonistic properties of the suramin analogue NF023 at heterologously expressed P2X receptors. Neuropharmacology, 38 (1): 141-9. [PMID:10193905]
29. Stokes, L; Jiang, LH; Alcaraz, L; Bent, J; Bowers, K; Fagura, M; Furber, M; Mortimore, M; Lawson, M; Theaker, J; et al.. (2006) Characterization of a selective and potent antagonist of human P2X(7) receptors, AZ11645373. Br. J. Pharmacol., 149 (7): 880-7. [PMID:17031385]
30. Surprenant, A; North, RA. (2009) Signaling at purinergic P2X receptors. Annu. Rev. Physiol., 71: 333-59. [PMID:18851707]
31. Virginio, C; Robertson, G; Surprenant, A; North, RA. (1998) Trinitrophenyl-substituted nucleotides are potent antagonists selective for P2X1, P2X3, and heteromeric P2X2/3 receptors. Mol. Pharmacol., 53 (6): 969-73. [PMID:9614197]
|
 @GuidetoPHARM  Like us on Facebook Privacy and Cookie Policy |
A317491 and RO3 also block the P2X2:P2X3 heteromultimer [8,12]. 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 [5,7,11].
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 r & hP2X1–3,5 and hP2X4, but not rP2X4,6,7 [1], and can also inhibit ATPase activity [4]. Ip5I is inactive at rP2X2, an antagonist at rP2X3 (pIC50 5.6) and enhances agonist responses at rP2X4 [18]. Antagonist potency of NF023 at recombinant P2X2, P2X3 and P2X5 is two orders of magnitude lower than that at P2X1 receptors [28]. The P2X7 receptor may be inhibited in a non-competitive manner by the protein kinase inhibitors KN62 and chelerythrine [27], while the p38 MAP kinase inhibitor GTPγS and the cyclic imide AZ11645373 show a species-dependent non-competitive action [6,22-23,29]. The pH-sensitive dye used in culture media, phenol red, is also reported to inhibit P2X1 and P2X3 containing channels [19]. Some recombinant P2X receptors expressed to high density bind [35S]ATPγS and [3H]αβ-meATP, although the latter can also bind to 5′-nucleotidase [21]. [3H]A317491 and [3H]A804598 have been used as high affinity antagonist radioligands for P2X3 (and P2X2/3) and P2X7 receptors, respectively [7].