Skip to main content

Advertisement

SpringerLink
Log in

Molecular properties of P2X receptors

  • Invited Review
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

P2X receptors for adenosine tri-phosphate (ATP) are a distinct family of ligand-gated cation channels with two transmembrane domains, intracellular amino and carboxy termini and a large extracellular ligand binding loop. Seven genes (P2X1-7) have been cloned and the channels form as either homo or heterotrimeric channels giving rise to a wide range of phenotypes. This review aims to give an account of recent work on the molecular basis of the properties of P2X receptors. In particular, to consider emerging information on the assembly of P2X receptor subunits, channel regulation and desensitisation, targeting, the molecular basis of drug action and the functional contribution of P2X receptors to physiological processes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Valera S, Hussy N, Evans RJ, Adami N, North RA, Surprenant A, Buell G (1994) A new class of ligand-gated ion channel defined by P2X receptor for extraxcellular ATP. Nature 371:516–519

    PubMed  CAS  Google Scholar 

  2. Brake AJ, Wagenbach MJ, Julius D (1994) New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor. Nature 371:519–523

    PubMed  CAS  Google Scholar 

  3. Khakh BS, Burnstock G, Kennedy C, King BF, North RA, Seguela P, Voigt M, Humphrey PPA (2001) International Union of Pharmacology, XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits. Pharmacol Rev 53:107–118

    PubMed  CAS  Google Scholar 

  4. North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067

    PubMed  CAS  Google Scholar 

  5. Burnstock G (2002) Potential therapeutic targets in the rapidly expanding field of purinergic signalling. Clin Med 2:45–53

    Article  PubMed  CAS  Google Scholar 

  6. Egan TM, Cox JA, Voigt MM (2004) Molecular Structure of P2X Receptors. Curr Top Med Chem 4:821–829

    Article  PubMed  CAS  Google Scholar 

  7. Stojilkovic SS, Tomic M, He ML, Yan Z, Koshimizu TA, Zemkova H (2005) Molecular dissection of purinergic P2X receptor channels. Ann N Y Acad Sci 1048:116–130

    Article  PubMed  CAS  Google Scholar 

  8. Khakh BS (2001) Molecular physiology of P2X receptor and ATP signalling at synapses. Nat Rev Neurosci 2:165–174

    PubMed  CAS  Google Scholar 

  9. Vial C, Roberts JA, Evans RJ (2004) Molecular properties of ATP-gated P2X receptor ion channel. Trends Pharmacol Sci 25:487–493

    Article  PubMed  CAS  Google Scholar 

  10. Surprenant A, Buell G, North RA (1995) P2X receptors bring new structure to ligand-gated ion channels. Trends Neurosci 18:224–229

    PubMed  CAS  Google Scholar 

  11. Newbolt A, Stoop R, Virginio C, Surprenant A, North RA, Buell G, Rassendren F (1998) Membrane topology of an ATP-gated ion channel (P2X receptor). J Biol Chem 273:15177–15182

    Article  PubMed  CAS  Google Scholar 

  12. Lewis C, Neidhart S, Holy C, North RA, Buell G, Surprenant A (1995) Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature 377:432–435

    Article  PubMed  CAS  Google Scholar 

  13. Nicke A, Baumert H, 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 17:3016–3028

    Article  PubMed  CAS  Google Scholar 

  14. Aschrafi A, Sadtler S, Niculescu C, Rettinger J, Schmalzing G (2004) Trimeric architecture of homomeric P2X2 and heteromeric P2X1+2 receptor subtypes. J Mol Biol 342:333–343

    Article  PubMed  CAS  Google Scholar 

  15. Stoop R, Thomas S, Rassendren F, Kawashima E, Buell G, Surprenant A, North RA (1999) Contribution of individual subunits to the multimeric P2X(2) receptor: estimates based on methanethiosulfonate block at T336C. Mol Pharmacol 56:973–981

    PubMed  CAS  Google Scholar 

  16. Nagaya N, Tittle RK, Saar N, Dellal SS, Hume RI (2005) An intersubunit Zn2+ binding site in rat P2X2 receptors. J Biol Chem 280(28):25982–25993

    Article  PubMed  CAS  Google Scholar 

  17. Bean BP (1990) ATP-activated channels in rat and bullfrog sensory neurons: concentration dependence and kinetics. J Neurosci 10(1):1–10

    PubMed  CAS  Google Scholar 

  18. Ding S, Sachs F (1999) Single channel properties of P2X2 purinoceptors. J Gen Physiol 113:695–720

    Article  PubMed  CAS  Google Scholar 

  19. Gouaux E (2004) Structure and function of AMPA receptors. J Physiol 554:249–253

    Article  PubMed  CAS  Google Scholar 

  20. Kim M, Yoo OK, Choe S (1997) Molecular assembly of the extracellular domain of P2X2, an ATP-gated ion channel. Biochem Biophys Res Commun 240:618–622

    Article  PubMed  CAS  Google Scholar 

  21. Barrera NP, Ormond SJ, Henderson RM, Murrell-Lagnado RD, Edwardson JM (2005) AFM imaging demonstrates that P2X2 receptors are trimers, but that P2X6 receptor subunits do not oligomerize. J Biol Chem 280:10759–10765

    Article  PubMed  CAS  Google Scholar 

  22. Nakazawa K, Yamakoshi Y, Tsuchiya T, Ohno Y (2005) Purification and aqueous phase atomic force microscopic observation of recombinant P2X2 receptor. Eur J Pharmacol 518:107–110

    Article  PubMed  CAS  Google Scholar 

  23. Unwin N (2005) Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J Mol Biol 346:967–989

    Article  PubMed  CAS  Google Scholar 

  24. Mio K, Kubo Y, Ogura T, Yamamoto T, Sato C (2005) Visualization of the trimeric P2X(2) receptor with a crown-capped extracellular domain. Biochem Biophys Res Commun 337:998–1005

    Article  PubMed  CAS  Google Scholar 

  25. Torres GE, Egan TM, Voigt MM (1999) Hetero-oligomeric assembly of P2X receptor subunits. J Biol Chem 274:6653–6659

    Article  PubMed  CAS  Google Scholar 

  26. Nicke A, Kerschensteiner D, Soto F (2005) Biochemical and functional evidence for heteromeric assembly of P2X1 and P2X4 subunits. J Neurochem 92:925–933

    Article  PubMed  CAS  Google Scholar 

  27. Torres GE, Egan TM, Voigt MM (1999) Identification of a domain involved in ATP-gated ionotropic receptor subunit assembly. J Biol Chem 274:22359–22365

    Article  PubMed  CAS  Google Scholar 

  28. Brown SG, Townsend-Nicholson A, Jacobson KA, Burnstock G, King BF (2002) Heteromultimeric P2X(1/2) receptors show a novel sensitivity to extracellular pH. J Pharmacol Exp Ther 300:673–680

    Article  PubMed  CAS  Google Scholar 

  29. Haines WR, Torres GE, Voigt MM, Egan TM (1999) Properties of the novel ATP-gated ionotropic receptor composed of the P2X1 and P2X5 isoforms. Mol Pharmacol 56:720–727

    PubMed  CAS  Google Scholar 

  30. Surprenant A, Schneider DA, Wilson HA, Galligan JJ, North RA (2000) Functional properties of heteromeric P2X(1/5) receptors expressed in HEK cells and excitatory junction potentials in guinea-pig submucosal arterioles. J Auton Nerv Syst 81:249–263

    Article  PubMed  CAS  Google Scholar 

  31. King BF, Townsend-Nicholson A, Wildman SS, Thomas T, Spyer KM, Burnstock G (2000) Coexpression of rat P2X2 and P2X6 subunits in Xenopus oocytes. J Neurosci 20:4871–4877

    PubMed  CAS  Google Scholar 

  32. Le K-T, Babinski K, Seguela P (1998) Central P2X4 and P2X6 channel subunits coassemble into a novel heteromeric ATP receptor. J Neurosci 18:7152–7159

    PubMed  CAS  Google Scholar 

  33. Jiang LH, Kim M, Spelta V, Bo X, Surprenant A, North RA (2003) Subunit arrangement in P2X receptors. J Neurosci 23:8903–8910

    PubMed  CAS  Google Scholar 

  34. Cook SP, Vulchanova L, Hargreaves KM, Elde RP, McCleskey EW (1997) Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 387:505–508

    Article  PubMed  CAS  Google Scholar 

  35. Thomas S, Virginio C, North RA, Surprenant A (1998) The antagonist trinitrophenyl-ATP reveals co-existence of distinct P2X receptor channels in rat nodose neurons. J Physiol 509:411–417

    Article  PubMed  CAS  Google Scholar 

  36. Grubb BD, Evans RJ (1998) Characterization of cultured dorsal root ganglion neuron P2X receptors. Eur J Neurosci 11:149–154

    Article  Google Scholar 

  37. Werner P, Seward EP, Buell G, North RA (1996) Domains of P2X receptors involved in desensitization. Proc Natl Acad Sci U S A 93:15485–15490

    Article  PubMed  CAS  Google Scholar 

  38. Brandle U, Spielmanns P, Osteroth R, Sim J, Surprenant A, Buell G, Ruppersberg JP, Plinkert PK, Zenner H-P, Glowatzki E (1997) Desensitisation of the P2X2 receptor controlled by alternative splicing. FEBS Lett 404:294–298

    Article  PubMed  CAS  Google Scholar 

  39. Simon J, Kidd EJ, Smith FM, Chessel IP, Murrell-Lagnado R, Humphrey PPA, Barnard EA (1997) Localization and functional expression of splice variants of the P2X2 receptor. Mol Pharmacol 52:237–248

    PubMed  CAS  Google Scholar 

  40. Smith FM, Humphry PPA, Murrell-Lagnado RD (1999) Identification of amino acids within the P2X2 receptor C-terminus that regulate desensitisation. J Physiol 520:91–99

    Article  PubMed  CAS  Google Scholar 

  41. Eickhorst AN, Berson A, Cockayne D, Lester HA, Khakh BS (2002) Control of P2X(2) channel permeability by the cytosolic domain. J Gen Physiol 120:119–131

    PubMed  CAS  Google Scholar 

  42. Toulme E, Soto F, Garret M, Boue-Grabot E (2005) Functional properties of internalization-deficient P2X4 receptors reveal a novel mechanism of ligand-gated channel facilitation by ivermectin. Mol Pharmacol 69(2):576–587

    Article  PubMed  CAS  Google Scholar 

  43. Boue-Grabot E, Archambault V, Seguela P (2000) A protein kinase C site highly conserved in P2X subunits controls the desensitisation kinetics of P2X2 ATP-gated channels. J Biol Chem 275:10190–10195

    Article  PubMed  CAS  Google Scholar 

  44. Paukert M, Osteroth R, Geisler H-S, Brandle U, Glowatzki E, Ruppersberg JP, Grunder S (2001) Inflamatory mediators potentiate ATP-gated channels through the P2X3 subunit. J Biol Chem 276:21077–21082

    Article  PubMed  CAS  Google Scholar 

  45. Ennion SJ, Evans RJ (2002) P2X(1) receptor subunit contribution to gating revealed by a dominant negative PKC mutant. Biochem Biophys Res Commun 291:611–616

    Article  PubMed  CAS  Google Scholar 

  46. Ennion S, Hagan S, Evans RJ (2000) The role of positively charged amino acids in ATP recognition by human P2X1 receptors. J Biol Chem 275:29361–29367

    Article  PubMed  CAS  Google Scholar 

  47. Zemkova H, He ML, Koshimizu TA, Stojilkovic SS (2004) Identification of ectodomain regions contributing to gating, deactivation, and resensitization of purinergic P2X receptors. J Neurosci 24:6968–6978

    Article  PubMed  CAS  Google Scholar 

  48. Rettinger J, Schmalzing G (2003) Activation and desensitization of the recombinant P2X1 receptor at nanomolar ATP concentrations. J Gen Physiol 121:451–461

    Article  PubMed  CAS  Google Scholar 

  49. Rettinger J, Schmalzing G (2004) Desensitization masks nanomolar potency of ATP for the P2X1 receptor. J Biol Chem 279:6426–6433

    Article  PubMed  CAS  Google Scholar 

  50. Sokolova E, Skorinkin A, Fabbretti E, Masten L, Nistri A, Giniatullin R (2004) Agonist-dependence of recovery from desensitization of P2X3 receptors provides a novel and sensitive approach for their rapid up or downregulation. Br J Pharmacol 141:1048–1058

    Article  PubMed  CAS  Google Scholar 

  51. Pratt EB, Brink TS, Bergson P, Voigt MM, Cook SP (2005) Use-dependent inhibition of P2X3 receptors by nanomolar agonist. J Neurosci 25:7359–7365

    Article  PubMed  CAS  Google Scholar 

  52. Dunn PM, Liu M, Zhong Y, King BF, Burnstock G (2000) Diinosine pentaphosphate: an antagonist which discriminates between recombinant P2X3 and P2X2/3 receptors and between two P2X receptors in rat sensory neurones. Br J Pharmacol 130:1378–1384

    Article  PubMed  CAS  Google Scholar 

  53. Ford KK, Matchett M, Krause JE, Yu W (2005) The P2X3 Antagonist P1, P5-Di[inosine-5′] pentaphosphate binds to the desensitized state of the receptor in rat dorsal root ganglion neurons. J Pharmacol Exp Ther 315:405–413

    Article  PubMed  CAS  Google Scholar 

  54. Cook SP, McCleskey EW (1997) Desensitization, recovery and Ca(2+)-dependent modulation of ATP-gated P2X receptors in nociceptors. Neuropharmacology 36:1303–1308

    Article  PubMed  CAS  Google Scholar 

  55. Cook SP, Rodland KD, McCleskey EW (1998) A memory for extracellular Ca2+ by speeding recovery of P2X receptors from desensitisation. J Neurosci 18:9238–9244

    PubMed  CAS  Google Scholar 

  56. Fabbretti E, Sokolova E, Masten L, D’Arco M, Fabbro A, Nistri A, Giniatullin R (2004) Identification of negative residues in the P2X3 ATP receptor ectodomain as structural determinants for desensitization and the Ca2+-sensing modulatory sites. J Biol Chem 279:53109–53115

    Article  PubMed  CAS  Google Scholar 

  57. Wildman SS, Brown SG, Rahman M, Noel CA, Churchill L, Burnstock G, Unwin RJ, King BF (2002) Sensitization by extracellular Ca(2+) of Rat P2X(5) Receptor and Its Pharmacological Properties Compared with Rat P2X(1). Mol Pharmacol 62:957–966

    Article  PubMed  CAS  Google Scholar 

  58. Lewis CJ, Evans RJ (2000) Lack of run-down of smooth muscle P2X receptor currents recorded with the amphotericin permeabilised patch technique; physioloigcal and pharmacological characterisation of the properties of mesenteric artery P2X receptor ion channels. Br J Pharmacol 131:1659–1666

    Article  PubMed  CAS  Google Scholar 

  59. Nakazawa K, Inoue K, Koizumi S (1994) Facilitation by 5-hydroxytryptamine of ATP-activated current in rat pheochromocytoma cells. Pflugers Arch 427:492–499

    Article  PubMed  CAS  Google Scholar 

  60. Nakazawa K, Fujimori K, Takanaka A, Inoue K (1991) Comparison of adenosine triphosphate- and nicotine-activated inward currents in rat phaeochromocytoma cells. J Physiol 434:647–660

    PubMed  CAS  Google Scholar 

  61. Nakazawa K (1994) ATP-activated current and its interaction with acetylcholine-activated current in rat sympathetic neurons. J Neurosci 14:740–750

    PubMed  CAS  Google Scholar 

  62. Vial C, Tobin AB, Evans RJ (2004) G-protein-coupled receptor regulation of P2X(1) receptors does not involve direct channel phosphorylation. Biochem J 382:101–110

    Article  PubMed  CAS  Google Scholar 

  63. Ase AR, Raouf R, Belanger D, Hamel E, Seguela P (2005) Potentiation of P2X1 ATP-gated currents by 5-hydroxytryptamine 2A receptors involves diacylglycerol-dependent kinases and intracellular calcium. J Pharmacol Exp Ther 315:144–154

    Article  PubMed  CAS  Google Scholar 

  64. Adinolfi E, Kim M, Young MT, Di Virgilio F, Surprenant A (2003) Tyrosine phosphorylation of HSP90 within the P2X7 receptor complex negatively regulates P2X7 receptors. J Biol Chem 278:37344–37351

    Article  PubMed  CAS  Google Scholar 

  65. Chow Y-W, Wang H-L (1998) Functional modulation of P2X2 receptors by cyclic AMP-dependent protein kinase. J Neurochem 70:2606–2612

    Article  PubMed  CAS  Google Scholar 

  66. Xu GY, Huang LY (2004) Ca2+/calmodulin-dependent protein kinase II potentiates ATP responses by promoting trafficking of P2X receptors. Proc Natl Acad Sci U S A 101(32):11866–11873

    Google Scholar 

  67. Wirkner K, Stanchev D, Koles L, Klebingat M, Dihazi H, Flehmig G, Vial C, Evans RJ, Furst S, Mager PP, Eschrich K, Illes P (2005) Regulation of human recombinant P2X3 receptors by ecto-protein kinase C. J Neurosci 25:7734–7742

    Article  PubMed  CAS  Google Scholar 

  68. Searl TJ, Redman RS, Silinsky EM (1998) Mutual occlusion of P2X ATP receptors and nicotinic receptors on sympathetic neurons of guinea-pig. J Physiol 510:783–791

    Article  PubMed  CAS  Google Scholar 

  69. Zhou X, Galligan JJ (1998) Non-additive interaction between nicotinic cholinergic and P2X purine receptors in guinea-pig enteric neurons in culture. J Physiol 513(3):685–697

    Article  PubMed  CAS  Google Scholar 

  70. Barajas-Lopez C, Espinosa-Luna R, Zhu Y (1998) Functional interactions between nicotinic and P2X channels in short-term cultures of guinea-pig submucosal neurons. J Physiol 513(3):671–683

    Article  PubMed  CAS  Google Scholar 

  71. Khakh BS, Zhou X, Sydes J, Galligan JJ, Lester HA (2000) State-dependent cross-inhibition between transmitter-gated cation channels. Nature 406:405–410

    Article  PubMed  CAS  Google Scholar 

  72. Barajas-Lopez C, Montano LM, Espinosa-Luna R (2002) Inhibitory interactions between 5-HT3 and P2X channels in submucosal neurons. Am J Physiol Gastrointest Liver Physiol 283:G1238–G1248

    PubMed  CAS  Google Scholar 

  73. Boue-Grabot E, Barajas-Lopez C, Chakfe Y, Blais D, Belanger D, Emerit MB, Seguela P (2003) Intracellular cross talk and physical interaction between two classes of neurotransmitter-gated channels. J Neurosci 23:1246–1253

    PubMed  CAS  Google Scholar 

  74. Sokolova E, Nistri A, Giniastullin R (2001) Negative cross talk between anionic GABAA and cationic P2X ionotropic receptors of dorsal root ganglion neurons. J Neurosci 21:4958–4968

    PubMed  CAS  Google Scholar 

  75. Boue-Grabot E, Emerit MB, Toulme E, Seguela P, Garret M (2004) Cross-talk and co-trafficking between {rho}1/GABA receptors and ATP-gated channels. J Biol Chem 279:6967–6975

    Article  PubMed  CAS  Google Scholar 

  76. Boue-Grabot E, Toulme E, Emerit MB, Garret M (2004) Subunit-specific coupling between gamma-aminobutyric acid type A and P2X2 receptor channels. J Biol Chem 279:52517–52525

    Article  PubMed  CAS  Google Scholar 

  77. Khakh BS, Fisher JA, Nashmi R, Bowser DN, Lester HA (2005) An angstrom scale interaction between plasma membrane ATP-gated P2X2 and alpha4beta2 nicotinic channels measured with fluorescence resonance energy transfer and total internal reflection fluorescence microscopy. J Neurosci 25:6911–6920

    Article  PubMed  CAS  Google Scholar 

  78. Kim M, L-H. Jiang, Wilson HL, North RA, Surprenant A (2001) Proteomic and functional evidence for a P2X7 receptor signalling complex. EMBO J 20:6347–6358

    Article  PubMed  CAS  Google Scholar 

  79. Wilson HL, Wilson SA, Surprenant A, North RA (2002) Epithelial membrane proteins induce membrane blebbing and interact with the P2X7 receptor C terminus. J Biol Chem 277:34017–34023

    Article  PubMed  CAS  Google Scholar 

  80. Gendreau S, Schirmer J, Schmalzing G (2003) Identification of a tubulin binding motif on the P2X2 receptor. J Chromatogr B Analyt Technol Biomed Life Sci 786:311–318

    PubMed  CAS  Google Scholar 

  81. Masin M, Kerschensteiner D, Dumke K, Rubio ME, Soto F (2006) Fe65 interacts with P2X2 subunits at excitatory synapses and modulates receptor function. J Biol Chem 281(7):4100–4108

    Article  PubMed  CAS  Google Scholar 

  82. Royle SJ, Bobanovic LK, Murrell-Lagnado RD (2002) Identification of a non-canonical tyrosine-based endocytic motif in an ionotropic receptor. J Biol Chem 277:35378–35385

    Article  PubMed  CAS  Google Scholar 

  83. Royle SJ, Qureshi OS, Bobanovic LK, Evans PR, Owen DJ, Murrell-Lagnado RD (2005) Non-canonical YXXGPhi endocytic motifs: recognition by AP2 and preferential utilization in P2X4 receptors. J Cell Sci 118:3073–3080

    Article  PubMed  CAS  Google Scholar 

  84. Chaumont S, Jiang LH, Penna A, North RA, Rassendren F (2004) Identification of a trafficking motif involved in the stabilization and polarization of P2X receptors. J Biol Chem 279:29628–29638

    Article  PubMed  CAS  Google Scholar 

  85. Khakh BS, Procotor WR, Dunwiddie TV, Labarca C, Lester HA (1999) Allosteric control of gating and kinetics at P2X4 receptor channels. J Neurosci 19:7289–7299

    PubMed  CAS  Google Scholar 

  86. Priel A, Silberberg SD (2004) Mechanism of ivermectin facilitation of human P2X4 receptor channels. J Gen Physiol 123:281–293

    Article  PubMed  CAS  Google Scholar 

  87. Wiley JS, Dao-Ung LP, Li C, Shemon AN, Gu BJ, Smart ML, Fuller SJ, Barden JA, Petrou S, Sluyter R (2003) An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor. J Biol Chem 278:17108–17113

    Article  PubMed  CAS  Google Scholar 

  88. Denlinger LC, Sommer JA, Parker K, Gudipaty L, Fisette PL, Watters JW, Proctor RA, Dubyak GR, Bertics PJ (2003) Mutation of a dibasic amino acid motif within the C terminus of the P2X7 nucleotide receptor results in trafficking defects and impaired function. J Immunol 171:1304–1311

    PubMed  CAS  Google Scholar 

  89. Wildman SS, Marks J, Churchill LJ, Peppiatt CM, Chraibi A, Shirley DG, Horisberger JD, King BF, Unwin RJ (2005) Regulatory interdependence of cloned epithelial Na+ channels and P2X receptors. J Am Soc Nephrol 16:2586–2597

    Article  PubMed  CAS  Google Scholar 

  90. Ding S, Sachs F (2005) Evidence for non-independent gating of P2X2 receptors expressed in Xenopus oocytes. BMC Neurosci 3:17

    Article  Google Scholar 

  91. Clyne JD, Brown TC, Hume RI (2003) Expression level dependent changes in the properties of P2X2 receptors. Neuropharmacology 44:403–412

    Article  PubMed  CAS  Google Scholar 

  92. Fujiwara Y, Kubo Y (2004) Density-dependent changes of the pore properties of the P2X2 receptor channel. J Physiol 558:31–43

    Article  PubMed  CAS  Google Scholar 

  93. Khakh BS, Gittermann D, Cockayne DA, Jones A (2003) ATP modulation of excitatory synapses onto interneurons. J Neurosci 23:7426–7437

    PubMed  CAS  Google Scholar 

  94. Pike LJ (2004) Lipid rafts: heterogeneity on the high seas. Biochem J 378:281–292

    Article  PubMed  CAS  Google Scholar 

  95. Vial C, Evans RJ (2005) Disruption of lipid rafts inhibits P2X1 receptor-mediated currents and arterial vasoconstriction. J Biol Chem 280:30705–30711

    Article  PubMed  CAS  Google Scholar 

  96. Vacca F, Amadio S, Sancesario G, Bernardi G, Volonte C (2004) P2X3 receptor localizes into lipid rafts in neuronal cells. J Neurosci Res 76:653–661

    Article  PubMed  CAS  Google Scholar 

  97. Walker JE, Saraste M, Runswick MJ, Gay NJ (1982) Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP requiring enzymes and a common nucleotide binding fold. EMBO J 1:945–951

    PubMed  CAS  Google Scholar 

  98. Freist W, Verhey JF, Stuhmer W, Gauss DH (1998) ATP binding site of P2X channel proteins: structural similarities with class II aminoacyl-tRNA synthetases. FEBS Lett 434:61–65

    Article  PubMed  CAS  Google Scholar 

  99. Yan Z, Liang Z, Tomic M, Obsil T, Stojilkovic SS (2005) Molecular determinants of the agonist binding domain of a P2X receptor channel. Mol Pharmacol 67:1078–1088

    Article  PubMed  CAS  Google Scholar 

  100. Roberts JA, Evans RJ (2004) ATP binding at human P2X1 receptors: Contribution of aromatic and basic amino acids revealed using mutagenesis and partial agonists. J Biol Chem 279:9043–9055

    Article  PubMed  CAS  Google Scholar 

  101. Jiang L-H, Rassendren F, Surprenant A, North RA (2000) Identification of amino acid residues contributing to the ATP binding site of a purinergic P2X receptor. J Biol Chem 275:34190–34196

    Article  PubMed  CAS  Google Scholar 

  102. Worthington RA, Smart ML, Gu BJ, Williams DA, Petrou S, Wiley JS, Barden JA (2002) Point mutations confer loss of ATP-induced human P2X(7) receptor function. FEBS Lett 512:43–46

    Article  PubMed  CAS  Google Scholar 

  103. Gu BJ, Sluyter R, Skarratt KK, Shemon AN, Dao-Ung LP, Fuller SJ, Barden JA, Clarke AL, Petrou S, Wiley JS (2004) An Arg307 to Gln polymorphism within the ATP-binding site causes loss of function of the human P2X7 receptor. J Biol Chem 279:31287–31295

    Article  PubMed  CAS  Google Scholar 

  104. Li Z, Migita K, Samways DS, Voigt MM, Egan TM (2004) Gain and loss of channel function by alanine substitutions in the transmembrane segments of the rat ATP-gated P2X2 receptor. J Neurosci 24:9378–9386

    Google Scholar 

  105. Ennion SJ, Ritson J, Evans RJ (2001) Conserved negatively charged residues are not required for ATP action at P2X(1) receptors. Biochem Biophys Res Commun 289:700–704

    Article  PubMed  CAS  Google Scholar 

  106. Roberts JA, Evans RJ (2005) Contribution of conserved polar glutamine, asparagine and threonine residues and glycosylation to agonist action at human P2X1 receptors for ATP. J Neurochem 96(3):843–852

    Article  PubMed  CAS  Google Scholar 

  107. Tanner NK, Cordin O, Banroques J, Doere M, Linder P (2003) The Q motif: a newly identified motif in DEAD box helicases may regulate ATP binding and hydrolysis. Mol Cell 11:127–138

    Article  PubMed  CAS  Google Scholar 

  108. Ennion SJ, Evans RJ (2002) Conserved cysteine residues in the extracellular loop of the human P2X(1) receptor form disulfide bonds and are involved in receptor trafficking to the cell surface. Mol Pharmacol 61:303–311

    Article  PubMed  CAS  Google Scholar 

  109. Clyne JD, Wang LF, Hume RI (2002) Mutational analysis of the conserved cysteines of the rat P2X2 purinoceptor. J Neurosci 22:3873–3880

    PubMed  CAS  Google Scholar 

  110. Spelta V, Jiang LH, Bailey RJ, Surprenant A, North RA (2003) Interaction between cysteines introduced into each transmembrane domain of the rat P2X(2) receptor. Br J Pharmacol 138:131–136

    Article  PubMed  CAS  Google Scholar 

  111. Roberts JA, Evans RJ (2005) Mutagenesis studies of conserved proline residues of human P2X receptors for ATP indicate that proline 272 contributes to channel function. J Neurochem 92:1256–1264

    Article  PubMed  CAS  Google Scholar 

  112. Digby HR, Roberts JA, Sutcliffe MJ, Evans RJ (2005) Contribution of conserved glycine residues to ATP action at human P2X1 receptors: mutagenesis indicates that the glycine at position 250 is important for channel function. J Neurochem 95(6):1746–1754

    Article  PubMed  CAS  Google Scholar 

  113. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242

    Article  PubMed  CAS  Google Scholar 

  114. Gourine AV, Llaudet E, Dale N, Spyer KM (2005) ATP is a mediator of chemosensory transduction in the central nervous system. Nature 436:108–111

    Article  PubMed  CAS  Google Scholar 

  115. Zhao HB, Yu N, Fleming CR (2005) Gap junctional hemichannel-mediated ATP release and hearing controls in the inner ear. Proc Natl Acad Sci U S A 102(51):18724–18729

    Article  PubMed  CAS  Google Scholar 

  116. De Vuyst E, Decrock E, Cabooter L, Dubyak GR, Naus CC, Evans WH, Leybaert L (2006) Intracellular calcium changes trigger connexin 32 hemichannel opening. EMBO J 25:34–44

    Article  PubMed  CAS  Google Scholar 

  117. Benham CD (1986) ATP-gated cation channels in vascular smooth muscle cells. Biochem J 233:309–319

    PubMed  Google Scholar 

  118. Benham CD, Tsien RW (1987) A novel receptor-operated Ca2+-permeable channel activated by ATP in smooth muscle. Nature 328:275–278

    Article  PubMed  CAS  Google Scholar 

  119. Inoue R, Brading AF (1990) The properties of the ATP-induced depolarization and current in single cells isolated from the guinea-pig urinary bladder. Br J Pharmacol 100:619–625

    PubMed  CAS  Google Scholar 

  120. Mulryan K, Gitterman DP, Lewis CJ, Vial C, Leckie BJ, Cobb AL, Brown JE, Conley EC, Buell G, Pritchard CA, Evans RJ (2000) Reduced vas deferens contraction and male infertility in mice lacking P2X1 receptors. Nature 403:86–89

    Article  PubMed  CAS  Google Scholar 

  121. Vial C, Evans RJ (2000) P2X receptor expression in mouse urinary bladder and the requirement of P2X1 receptors for functional P2X receptor responses in the mouse urinary bladder smooth muscle. Br J Pharmacol 131:1489–1495

    Article  PubMed  CAS  Google Scholar 

  122. Vial C, Evans RJ (2002) P2X(1) receptor-deficient mice establish the native P2X receptor and a P2Y6-like receptor in arteries. Mol Pharmacol 62:1438–1445

    Article  PubMed  CAS  Google Scholar 

  123. Inscho EW, Cook AK, Imig JD, Vial C, Evans RJ (2003) Physiological role for P2X1 receptors in renal microvascular autoregulatory behavior. J Clin Invest 112:1895–1905

    Article  PubMed  CAS  Google Scholar 

  124. Inscho EW, Cook AK, Imig JD, Vial C, Evans RJ (2004) Renal autoregulation in P2X knockout mice. Acta Physiol Scand 181:445–453

    Article  PubMed  CAS  Google Scholar 

  125. Rolf MG, Mahaut-Smith MP (2002) Effects of enhanced P2X1 receptor Ca2+ influx on functional responses in human platelets. Thromb Haemost 88:495–502

    PubMed  CAS  Google Scholar 

  126. Hechler B, Lenain N, Marchese P, Vial C, Heim V, Freund M, Cazenave J-P, Cattaneo M, Ruggeri ZM, Evans RJ, Gachet C (2003) A role of the fast ATP-gated P2X1 cation channel in the thrombosis of small arteries in vivo. J Exp Med 198(4):661–667

    Article  PubMed  CAS  Google Scholar 

  127. Oury C, Kuijpers MJ, Toth-Zsamboki E, Bonnefoy A, Danloy S, Vreys I, Feijge MA, De Vos R, Vermylen J, Heemskerk JW, Hoylaerts MF (2003) Overexpression of the platelet P2X1 ion channel in transgenic mice generates a novel prothrombotic phenotype. Blood 101:3969–3976

    Article  PubMed  CAS  Google Scholar 

  128. Calvert JA, Evans RJ (2004) Heterogeneity of P2X receptors in sympathetic neurons: contribution of neuronal P2X1 receptors revealed using knockout mice. Mol Pharmacol 65:139–148

    Article  PubMed  CAS  Google Scholar 

  129. Watano T, Calvert JA, Vial C, Forsythe ID, Evans RJ (2004) P2X receptor subtype specific modulation of excitatory and inhibitory synaptic inputs in the rat brainstem. J Physiol 558:745–757

    Article  PubMed  CAS  Google Scholar 

  130. Rong W, Gourine AV, Cockayne DA, Xiang Z, Ford AP, Spyer KM, Burnstock G (2003) Pivotal role of nucleotide P2X2 receptor subunit of the ATP-gated ion channel mediating ventilatory responses to hypoxia. J Neurosci 23:11315–11321

    PubMed  CAS  Google Scholar 

  131. Ren J, Bian X, DeVries M, Schnegelsberg B, Cockayne DC, Ford AP, Galligan JJ (2003) P2X2 Subunits contribute to fast synaptic excitation in myenteric neurons of the mouse small intestine. J Physiol 551(1):309–322

    Article  PubMed  CAS  Google Scholar 

  132. Cockayne DA, Dunn PM, Zhong Y, Rong W, Hamilton SG, Knight GE, Ruan HZ, Ma B, Yip P, Nunn P, McMahon SB, Burnstock G, Ford AP (2005) P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP. J Physiol 567:621–639

    Article  PubMed  CAS  Google Scholar 

  133. Cockayne DA, Hamilton SG, Zhu Q-M, Dunn PM, Zhong Y, Novakovic S, Malmberg AB, Cain G, Berson A, Kassotakis L, Hedley L, Lachnit WG, Burnstock G, McMahon SB, Ford APDW (2000) Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 1011–1015

  134. Souslova V, Cesare P, Ding Y, Akopian AN, Stanfa L, Suzuki R, Carpenter K, Dickenson A, Boyce S, Hill R, Nebenius-Oosthuizen D, Smith AJH, Kidd EJ, Wood JN (2000) Warm-coding deficits and aberrant inflamatory pain in mice lacking P2X3 receptors. Nature 407:1015–1017

    Article  PubMed  CAS  Google Scholar 

  135. Honore P, Kage K, Mikusa J, Watt AT, Johnston JF, Wyatt JR, Faltynek CR, Jarvis MF, Lynch K (2002) Analgesic profile of intrathecal P2X(3) antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats. Pain 99:11–19

    Article  PubMed  CAS  Google Scholar 

  136. Barclay J, Patel S, Dorn G, Wotherspoon G, Moffatt S, Eunson L, Abdel’al S, Natt F, Hall J, Winter J, Bevan S, Wishart W, Fox A, Ganju P (2002) Functional downregulation of P2X3 receptor subunit in rat sensory neurons reveals a significant role in chronic neuropathic and inflammatory pain. J Neurosci 22:8139–8147

    PubMed  CAS  Google Scholar 

  137. Dorn G, Patel S, Wotherspoon G, Hemmings-Mieszczak M, Barclay J, Natt FJ, Martin P, Bevan S, Fox A, Ganju P, Wishart W, Hall J (2004) siRNA relieves chronic neuropathic pain. Nucleic Acids Res 32:e49

    Article  PubMed  CAS  Google Scholar 

  138. Bian X, Ren J, DeVries M, Schnegelsberg B, Cockayne DA, Ford AP, Galligan JJ (2003) Peristalsis is impaired in the small intestine of mice lacking the P2X3 subunit. J Physiol 551:309–322

    Article  PubMed  CAS  Google Scholar 

  139. Finger TE, Danilova V, Barrows J, Bartel DL, Vigers AJ, Stone L, Hellekant G, Kinnamon SC (2005) ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 310:1495–1499

    Article  PubMed  CAS  Google Scholar 

  140. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424:778–783

    PubMed  CAS  Google Scholar 

  141. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021

    Article  PubMed  CAS  Google Scholar 

  142. Yamamoto K, Sokabe T, Matsumoto T, Yoshimura K, Shibata M, Ohura N, Fukuda T, Sato T, Sekine K, Kato S, Isshiki M, Fujita T, Kobayashi M, Kawamura K, Masuda H, Kamiya A, Ando J (2006) Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice. Nat Med 12:133–137

    Article  PubMed  CAS  Google Scholar 

  143. Le K-T, Paquet M, Nouel D, Babinski K, Seguela P (1997) Primary structure and expression of a naturally truncated human P2X ATP receptor subunit from brain and immune system. FEBS Lett 418:195–199

    Article  PubMed  CAS  Google Scholar 

  144. Bo X, Jiang LH, Wilson HL, Kim M, Burnstock G, Surprenant A, North RA (2003) Pharmacological and biophysical properties of the human P2X5 receptor. Mol Pharmacol 63:1407–1416

    Article  PubMed  CAS  Google Scholar 

  145. Rijke BD, van Horssen-Zoetbrood A, Beekman JM, Otterud B, Maas F, Woestenenk R, Kester M, Leppert M, Schattenberg AV, de Witte T, van de Wiel-van Kemenade E, Dolstra H (2005) A frameshift polymorphism in P2X5 elicits an allogeneic cytotoxic T lymphocyte response associated with remission of chronic myeloid leukemia. J Clin Invest 115:3506–3516

    Article  PubMed  CAS  Google Scholar 

  146. Collo G, North RA, Kawashima E, Merlo-Pich E, Neidhart S, Surprenant A, Buell G (1996) Cloning of P2X5 and P2X6 receptors and the distribution and properties of an extended family of ATP-gated ion channels. J Neurosci 16:2495–2507

    PubMed  CAS  Google Scholar 

  147. Jones CA, Vial C, Sellers LA, Humphrey PP, Evans RJ, Chessell IP (2004) Functional regulation of P2X6 receptors by N-Linked glycosylation: identification of a novel {alpha}{beta}-methylene ATP-sensitive phenotype. Mol Pharmacol 65:979–985

    Article  PubMed  CAS  Google Scholar 

  148. Solle M, Labasi J, Perregaux DG, Stam E, Petrushova N, Koller BH, Griffiths RJ, Gabel CA (2001) Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem 276:125–132

    Article  PubMed  CAS  Google Scholar 

  149. Labasi JM, Petrushova N, Donovan C, McCurdy S, Lira P, Payette MM, Brissette W, Wicks JR, Audoly L, Gabel CA (2002) Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response. J Immunol 168:6436–6445

    PubMed  CAS  Google Scholar 

  150. Le Feuvre RA, Brough D, Iwakura Y, Takeda K, Rothwell NJ (2002) Priming of macrophages with lipopolysaccharide potentiates P2X7- mediated cell death via a caspase-1-dependent mechanism, independently of cytokine production. J Biol Chem 277:3210–3218

    Article  PubMed  CAS  Google Scholar 

  151. Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, Grahames CB, Casula MA, Yiangou Y, Birch R, Anand P, Buell GN (2005) Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114:386–396

    Article  PubMed  CAS  Google Scholar 

  152. Ke HZ, Qi H, Weidema AF, Zhang Q, Panupinthu N, Crawford DT, Grasser WA, Paralkar VM, Li M, Audoly LP, Gabel CA, Jee WS, Dixon SJ, Sims SM, Thompson DD (2003) Deletion of the P2X7 nucleotide receptor reveals its regulatory roles in bone formation and resorption. Mol Endocrinol 17:1356–1367

    Article  PubMed  CAS  Google Scholar 

  153. Korcok J, Raimundo LN, Ke HZ, Sims SM, Dixon SJ (2004) Extracellular nucleotides act through P2X7 receptors to activate NF-kappaB in osteoclasts. J Bone Miner Res 19:642–651

    PubMed  CAS  Google Scholar 

  154. Gartland A, Buckley KA, Hipskind RA, Perry MJ, Tobias JH, Buell G, Chessell I, Bowler WB, Gallagher JA (2003) Multinucleated osteoclast formation in vivo and in vitro by P2X7 receptor-deficient mice. Crit Rev Eukaryot Gene Expr 13:243–253

    Article  PubMed  CAS  Google Scholar 

  155. Li J, Liu D, Ke HZ, Duncan RL, Turner CH (2005) The P2X7 nucleotide receptor mediates skeletal mechanotransduction. J Biol Chem 280(52):42952–42959

    Article  PubMed  CAS  Google Scholar 

  156. Adriouch S, Dox C, Welge V, Seman M, Koch-Nolte F, Haag F (2002) Cutting edge: a natural P451L mutation in the cytoplasmic domain impairs the function of the mouse P2X7 receptor. J Immunol 169:4108–4112

    PubMed  CAS  Google Scholar 

  157. Gu BJ, Zhang W, Worthington RA, Sluyter R, Dao-Ung P, Petrou S, Barden JA, Wiley JS (2001) A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor. J Biol Chem 276:11135–11142

    Article  PubMed  CAS  Google Scholar 

  158. Saunders BM, Fernando SL, Sluyter R, Britton WJ, Wiley JS (2003) A loss-of-function polymorphism in the human P2X7 receptor abolishes ATP-mediated killing of mycobacteria. J Immunol 171:5442–5446

    PubMed  CAS  Google Scholar 

  159. Denlinger LC, Angelini G, Schell K, Green DN, Guadarrama AG, Prabhu U, Coursin DB, Bertics PJ, Hogan K (2005) Detection of human P2X7 nucleotide receptor polymorphisms by a novel monocyte pore assay predictive of alterations in lipopolysaccharide-induced cytokine production. J Immunol 174:4424–4431

    PubMed  CAS  Google Scholar 

  160. Sim JA, Young MT, Sung HY, North RA, Surprenant A (2004) Reanalysis of P2X7 receptor expression in rodent brain. J Neurosci 24:6307–6314

    Article  PubMed  CAS  Google Scholar 

  161. Kukley M, Stausberg P, Adelmann G, Chessell IP, Dietrich D (2004) Ecto-nucleotidases and nucleoside transporters mediate activation of adenosine receptors on hippocampal mossy fibers by P2X7 receptor agonist 2′-3′-O-(4-benzoylbenzoyl)-ATP. J Neurosci 24:7128–7139

    Article  PubMed  CAS  Google Scholar 

  162. Ashour F, Atterbury-Thomas AE, Deuchars J, Evans RJ (2006) An evaluation of antibody detection of the P2X1 receptor subunit in the CNS of wild type and P2X1-knockout mice. Neurosci Lett 397(1–2):120–125

    Article  PubMed  CAS  Google Scholar 

  163. North RA, Surprenant A (2000) Pharmacology of cloned P2X receptors. Annu Rev Pharmacol Toxicol 40:563–580

    Article  PubMed  CAS  Google Scholar 

  164. Stoop R, Surprenant A, North RA (1997) Different sensitivities to pH of ATP-indiced currents at four cloned P2X receptors. J Neurophysiol 78:1837–1840

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Wellcome Trust for support and Dr. Jurgen Rettinger for discussion on the time-course and modelling of desensitisation of P2X-receptor-mediated responses.

Author information

Authors and Affiliations

  1. Department of Cell Physiology & Pharmacology,Medical Sciences Building, University of Leicester, Leicester, LE1 9HN, UK

    Jonathan A. Roberts, Catherine Vial, Helen R. Digby, Kelvin C. Agboh, Hairuo Wen, Amelia Atterbury-Thomas & Richard J. Evans

Authors
  1. Jonathan A. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catherine Vial
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helen R. Digby
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kelvin C. Agboh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hairuo Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amelia Atterbury-Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Richard J. Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard J. Evans.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roberts, J.A., Vial, C., Digby, H.R. et al. Molecular properties of P2X receptors. Pflugers Arch - Eur J Physiol 452, 486–500 (2006). https://doi.org/10.1007/s00424-006-0073-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-006-0073-6

Keywords

Search

Navigation