Regulation of P2X3 receptor structure and function

CNS and Neurological Disorders - Drug Targets

Volumn 11, Issue 6, 2012, Pages 687-698

  Fabbretti, Elsa ^a   Nistri, Andrea ^b,c  

^a UNIVERSITY OF NOVA GORICA   (Slovenia)

^b SISSA   (Italy)

^c Istituto di Medicina Fisica e Riabilitazione   (Italy)

Author keywords

ATP; Migraine; Pain; Purinergic; Sensory neurons

Indexed keywords

4 AMINOBUTYRIC ACID; 4 AMINOBUTYRIC ACID A RECEPTOR; 4 AMINOBUTYRIC ACID B RECEPTOR; 5 [[(3 PHENOXYBENZYL) (1, 2, 3, 4 TETRAHYDRO 1 NAPHTHYL) AMINO] CARBONYL] TRIMELLITIC ACID; 5 [[(3 PHENOXYBENZYL)(1,2,3,4 TETRAHYDRO 1 NAPHTHYL)AMINO]CARBONYL]TRIMELLITIC ACID; ANTINOCICEPTIVE AGENT; BRADYKININ; BRAIN DERIVED NEUROTROPHIC FACTOR; CALCINEURIN; CALCITONIN GENE RELATED PEPTIDE; CALCIUM CALMODULIN DEPENDENT PROTEIN KINASE II; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; CYCLIN DEPENDENT KINASE 5; MEMBRANE PROTEIN; NERVE GROWTH FACTOR; NERVE GROWTH FACTOR RECEPTOR; NICOTINIC RECEPTOR; NORADRENALIN; PHOSPHATASE; PHOSPHOTRANSFERASE; PROSTAGLANDIN E2; PROTEIN KINASE; PURINERGIC P2X3 RECEPTOR; PURINERGIC P2Y RECEPTOR; PUROTOXIN 1; RAB7 PROTEIN; TUBULIN; TUMOR NECROSIS FACTOR ALPHA; UBIQUITIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANILLOID RECEPTOR 1;

AMINO ACID SEQUENCE; ARTICLE; CELL MIGRATION; CHRONIC PAIN; HUMAN; INFLAMMATORY PAIN; LIPID RAFT; NONHUMAN; NUCLEOTIDE SEQUENCE; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; RECEPTOR BINDING; RECEPTOR DOWN REGULATION; RECEPTOR SENSITIVITY;

ADENOSINE TRIPHOSPHATE; AMINO ACID SEQUENCE; ANIMALS; HUMANS; MICE; MOLECULAR SEQUENCE DATA; MOLECULAR TARGETED THERAPY; NOCICEPTIVE PAIN; PAIN; PROTEIN MULTIMERIZATION; PURINERGIC P2X RECEPTOR ANTAGONISTS; RECEPTORS, PURINERGIC P2X3; SENSORY RECEPTOR CELLS;

EID: 84869033549     PISSN: 18715273     EISSN: 19963181     Source Type: Journal    
DOI: 10.2174/187152712803581029     Document Type: Article

References (140)

1. Burnstock, G. Physiology and pathophysiology of purinergic neurotransmission. Physiol. Rev., 2007, 87(2), 659-797.
2. Chen, C.C.; Akopian, A.N.; Sivilotti, L.; Colquhoun, D.; Burnstock, G.; Wood, JN. A P2X purinoceptor expressed by a subset of sensory neurons. Nature, 1995, 377(6548), 428-431.
3. Franke, H.; Krügel, U.; Grosche, J; Heine, C.; Härtig, W.; Allgaier, C.; Illes, P. P2Y receptor expression on astrocytes in the nucleus accumbens of rats. Neuroscience, 2004, 127(2), 431-441.
4. Burnstock, G. Purinergic receptors and pain. Curr. Pharm. Des., 2009, 15(15), 1717-1735.
5. Dunn, P.M.; Zhong, Y.; Burnstock, G. P2X receptors in peripheral neurons. Prog. Neurobiol., 2001, 65(2), 107-134.
6. North, R.A. P2X3 receptors and peripheral pain mechanisms. J. Physiol., 2004, 554(2), 301-308.
7. Vulchanova, L.; Riedl, M.S.; Shuster, S. J; Buell, G.; Surprenant, A.; North, R.A.; Elde, R. Immunohistochemical study of the P2X2 and P2X3 receptor subunits in rat and monkey sensory neurons and their central terminals. Neuropharmacology, 1997, 36(9), 1229-1242.
8. Vulchanova, L.; Riedl, M.S.; Shuster, S. J; Stone, L.S.; Hargreaves, K.M.; Buell, G.; Surprenant, A.; North, R.A.; Elde, R. P2X3 is expressed by DRG neurons that terminate in inner lamina II. Eur. J. Neurosci., 1998, 10(11), 3470-3478.
9. Khakh, B.S.; North, R.A. P2X receptors as cell-surface ATP sensors in health and disease. Nature, 2006, 442(7102), 527-532.
10. Wirkner, K.; Sperlagh, B.; Illes, P. P2X3 receptor involvement in pain states. Mol. Neurobiol., 2007, 36(2), 165-183.
11. Nakagawa, T.; Wakamatsu, K.; Zhang, N.; Maeda, S.; Minami, M.; Satoh, M.; Kaneko, S. Intrathecal administration of ATP produces long-lasting allodynia in rats, differential mechanisms in the phase of the induction and maintenance. Neuroscience, 2007, 147, 445-455.
12. Ford, A.P. In pursuit of P2X3 antagonists, novel therapeutics for chronic pain and afferent sensitization. Purinergic Signal., 2012, 8(S1), 3-26.
13. Gu, J.G.; MacDermott, A.B. Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses. Nature, 1997, 389(6652), 749-753.
14. Kaan, T.K.; Yip, P.K.; Grist, J.; Cefalu, J.S.; Nunn, P.A.; Ford, A.P.; Zhong, Y.; McMahon, S.B. Endogenous purinergic control of bladder activity via presynaptic P2X3 and P2X2/3 receptors in the spinal cord. J. Neurosci., 2010, 30(12), 4503-4507.
15. Tsuda, M.; Ueno, S.; Inoue, K. In vivo pathway of thermal hyperalgesia by intrathecal administration of alpha, beta-methylene ATP in mouse spinal cord, involvement of the glutamate-NMDA receptor system. Br. J. Pharmacol., 1999, 127(2), 449-456.
16. 2+ entry through presynaptic P2X receptors elicits postsynaptic firing in the brainstem autonomic network. J. Neurosci., 2004, 24(12), 3125-3135.
17. Bardoni, R. Excitatory synaptic transmission in neonatal dorsal horn, NMDA and ATP receptors. News Physiol. Sci., 2001, 16, 95-100.
18. Rodrigues, R. J; Almeida, T.; Richardson, P. J; Oliveira, C.R.; Cunha, R.A. Dual presynaptic control by ATP of glutamate release via facilitatory P2X1, P2X2/3, and P2X3 and inhibitory P2Y1, P2Y2, and/or P2Y4 receptors in the rat hippocampus. J. Neurosci., 2005, 25(27), 6286-6295.
19. Khakh, B.S. Molecular physiology of P2X receptors and ATP signalling at synapses. Nat. Rev. Neurosci., 2001, 2(3), 165-174.
20. Vacca, F.; D'Ambrosi, N.; Nestola, V.; Amadio, S.; Giustizieri, M.; Cucchiaroni, M.L.; Tozzi, A.; Velluz, M.C.; Mercuri, N.B.; Volonté, C. N-Glycans mutations rule oligomeric assembly and functional expression of P2X3 receptor for extracellular ATP. Glycobiology, 2011, 21(5), 634-643.
21. Kawate, T.; Michel, J.C.; Birdsong, W.T.; Gouaux, E. Crystal structure of the ATP-gated P2X4 ion channel in the closed state. Nature, 2009, 460(7255), 592-598.
22. Jiang, R.; Taly, A.; Lemoine, D.; Martz, A.; Cunrath, O.; Grutter, T. Tightening of the ATP-binding sites induces the opening of P2X receptor channels. EMBO J., 2012, 31(9), 2134-2143.
23. Hattori, M.; Gouaux, E. Molecular mechanism of ATP binding and ion channel activation in P2X receptors. Nature, 2012, 485, 207-212.
24. Virginio, C.; North, R.A.; Surprenant, A. Calcium permeability and block at homomeric and heteromeric P2X2 and P2X3 receptors, and P2X receptors in rat nodose neurones. J. Physiol., 1998, 510(1), 27-35.
25. Riedel, T.; Wiese, S.; Leichsenring, A.; Illes, P. Effects of nucleotide analogs at the P2X3 receptor and its mutants identify the agonist binding pouch. Mol. Pharmacol., 2012, 82(1), 80-89.
26. Bodnar, M.; Wang, H.; Riedel, T.; Hintze, S.; Kato, E.; Fallah, G.; Gröger-Arndt, H.; Giniatullin, R.; Grohmann, M.; Hausmann, R.; Schmalzing, G.; Illes, P.; Rubini, P. Amino acid residues constituting the agonist binding site of the human P2X3 receptor. J. Biol. Chem., 2011, 286(4), 2739-2749.
27. Jindrichova, M.; Khafizov, K.; Skorinkin, A.; Fayuk, D.; Bart, G.; Zemkova, H.; Giniatullin, R. Highly conserved tyrosine 37 stabilizes desensitized states and restricts calcium permeability of ATP-gated P2X3 receptor. J. Neurochem., 2010, 119(4), 676-685.
28. 2+-dependent modulation of ATP-gated P2X receptors in nociceptors. Neuropharmacology, 1997, 36(9), 1303-1308.
29. Sokolova, E.; Skorinkin, A.; Fabbretti, E.; Masten, L.; Nistri, A.; Giniatullin, R. Agonist-dependence of recovery from desensitization of P2X3 receptors provides a novel and sensitive approach for their rapid up or downregulation. Br. J. Pharmacol., 2004, 141(6), 1048-1058.
30. Sokolova, E.; Skorinkin, A.; Moiseev, I.; Agrachev, A.; Nistri, A.; Giniatullin, R. Experimental and modeling studies of desensitization of P2X3 receptors. Mol. Pharmacol., 2006, 70(1), 373-382.
31. Zemkova, H.; He, M.L.; Koshimizu, TA.; Stojilkovic, S.S. Identification of ectodomain regions contributing to gating, deactivation, and resensitization of purinergic P2X receptors. J. Neurosci., 2004, 24(31), 6968-6978.
32. Petrenko, N.; Khafizov, K.; Tvrdonova, V.; Skorinkin, A.; Giniatullin, R. Role of the ectodomain serine 275 in shaping the binding pocket of the ATP-gated P2X3 receptor. Biochemistry, 2011, 50(39), 8427-8436.
33. 2+ on rat DRG neurons in culture. Neuropharmacology, 2003, 44(1), 132-140.
34. Pratt, E.B.; Brink, T.S.; Bergson, P.; Voigt, M.M.; Cook, S.P. Usedependent inhibition of P2X3 receptors by nanomolar agonist. J. Neurosci., 2005, 25(32), 7359-7365.
35. Fabbretti, E.; Sokolova, E.; Masten, L.; D'Arco, M.; Fabbro, A.; Nistri, A.; Giniatullin, R. Identification of negative residues in the P2X3 ATP receptor ectodomain as structural determinants for desensitization and the Ca2+-sensing modulatory sites. J. Biol. Chem., 2004, 279(51), 53109-53115.
36. Fabbretti, E.; D'Arco, M.; Fabbro, A.; Simonetti, M.; Nistri, A.; Giniatullin, R. Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. J. Neurosci., 2006, 26(23), 6163-6171.
37. D'Arco, M.; Giniatullin, R.; Simonetti, M.; Fabbro, A.; Nair, A.; Nistri, A.; Fabbretti, E. Neutralization of nerve growth factor induces plasticity of ATP-sensitive P2X3 receptors of nociceptive trigeminal ganglion neurons. J. Neurosci., 2007, 27(31), 8190-8201.
38. Wirkner, K.; Stanchev, D.; Köles, L.; Klebingat, M.; Dihazi, H.; Flehmig, G.; Vial, C.; Evans, RJ; Fürst, S.; Mager, PP.; Eschrich, K.; Illes, P. Regulation of human recombinant P2X3 receptors by ecto-protein kinase C. J. Neurosci., 2005, 25(34), 7734-7742.
39. Khmyz, V.; Maximyuk, O.; Teslenko, V.; Verkhratsky, A.; Krishtal, O. P2X3 receptor gating near normal body temperature. Pflugers Arch., 2008, 456(2), 339-347.
40. Jarvis, M.F. Contributions of P2X3 homomeric and heteromeric channels to acute and chronic pain. Expert Opin. Ther. Targets, 2003, 7(4), 513-522.
41. Grote, A.; Hans, M.; Boldogkoi, Z.; Zimmer, A.; Steinhäuser, C.; Jabs, R. Nanomolar ambient ATP decelerates P2X3 receptor kinetics. Neuropharmacology, 2008, 55(7), 1212-1218.
42. North, R.A.; Surprenant, A. Pharmacology of cloned P2X receptors. Annu. Rev. Pharmacol. Toxicol., 2000, 40, 563-580.
43. Brederson, J.D.; Jarvis, M.F. Homomeric and heteromeric P2X3 receptors in peripheral sensory neurons. Curr. Opin. Investig. Drugs, 2008, 9(7), 716-725.
44. Lewis, C.; Neidhart, S.; Holy, C.; North, R.A.; Buell, G.; Surprenant, A. Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature, 1995, 377, 432-435.
45. McGaraughty, S.; Jarvis, M.F. Antinociceptive properties of a nonnucleotide P2X3/P2X2/3 receptor antagonist. Drug News Perspect., 2005, 18(8), 501-507.
46. Fields, R.D.; Burnstock, G. Purinergic signalling in neuron-glia interactions. Nat. Rev. Neurosci., 2006, 7(6), 423-436.
47. Wilkinson, W.J.; Jiang, L.H.; Surprenant, A.; North, R.A. Role of ectodomain lysines in the subunits of the heteromeric P2X2/3 receptor. Mol. Pharmacol., 2006, 70(4), 1159-1163.
48. Hausmann, R.; Bodnar, M.; Woltersdorf, R.; Wang, H.; Fuchs, M.; Messemer, N.; Qin, Y.; Günther, J; Riedel, T.; Grohmann, M.; Nieber, K.; Schmalzing, G.; Rubini, P.; Illes, P. ATP binding site mutagenesis reveals different subunit stoichiometry of functional P2X2/3 and P2X2/6 receptors. J. Biol. Chem., 2012, 287(17), 13930-13943.
49. Liu, X. J; Gingrich, J.R.; Vargas-Caballero, M.; Dong, Y.N.; Sengar, A.; Beggs, S.; Wang, S.H.; Ding, H.K.; Frankland, P.W.; Salter, M.W. Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex. Nat. Med., 2008, 14(12), 1325-1332.
50. D'Arco, M.; Giniatullin, R.; Leone, V.; Carloni, P.; Birsa, N.; Nair, A.; Nistri, A.; Fabbretti, E. The C-terminal Src inhibitory kinase (Csk)-mediated tyrosine phosphorylation is a novel molecular mechanism to limit P2X3 receptor function in mouse sensory neurons. J. Biol. Chem., 2009, 284(32), 21393-21401.
51. Garcia-Guzman, M.; Stühmer, W.; Soto, F. Molecular characterization and pharmacological properties of the human P2X3 purinoceptor. Brain Res. Mol. Brain Res., 1997, 47(1-2), 59-66.
52. Sundukova, M.; Vilotti, S.; Abbate, R.; Fabbretti, E.; Nistri, A. Functional differences between ATP-Gated Human and Rat P2X3 Receptors are caused by critical residues of the Intracellular CTerminal Domain. J. Neurochem., 2012, 122(3), 557-567.
53. Liu, X.J.; Salter, M.W. Purines and pain mechanisms: recent developments. Curr. Opin. Investig. Drugs, 2005, 6(1), 65-75.
54. Cockayne, D.A.; Hamilton, S.G.; Zhu, Q.M.; Dunn, P.M.; Zhong, Y.; Novakovic, S.; Malmberg, A.B.; Cain, G.; Berson, A.; Kassotakis, L.; Hedley, L.; Lachnit, W.G.; Burnstock, G.; McMahon, S.B.; Ford, A.P. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature, 2000, 407(6807), 1011-1015.
55. Cockayne, D.A.; Dunn, P.M.; Zhong, Y.; Rong, W.; Hamilton, S.G.; Knight, G.E.; Ruan, H.Z.; Ma, B.; Yip, P.; Nunn, P.; McMahon, S.B.; Burnstock, G.; Ford, A.P. 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., 2005, 567(2), 621-639.
56. Souslova, V.; Cesare, P.; Ding, Y.; Akopian, A.N.; Stanfa, L.; Suzuki, R.; Carpenter, K.; Dickenson, A.; Boyce, S.; Hill, R.; Nebenuis-Oosthuizen, D.; Smith, A. J; Kidd, E. J; Wood, J.N. Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature, 2000, 407(6807), 1015-1017.
57. Jarvis, M.F. The neural-glial purinergic receptor ensemble in chronic pain states. Trends Neurosci., 2010, 33(1), 48-57.
58. van den Maagdenberg, A.M.; Pietrobon, D.; Pizzorusso, T.; KaJa, S.; Broos, L.A.; Cesetti, T.; van de Ven, R.C.; Tottene, A.; van der Kaa, J.; Plomp, J.J.; Frants, R.R.; Ferrari, M.D. A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron, 2004, 41(5), 701-710.
59. Tottene, A.; Conti, R.; Fabbro, A.; Vecchia, D.; Shapovalova, M.; Santello, M.; van den Maagdenberg, A.M.; Ferrari, M.D.; Pietrobon, D. Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Cav2.1 knockin migraine mice. Neuron, 2009, 61(5), 762-773.
60. Nair, A.; Simonetti, M.; Birsa, N.; Ferrari, M.D.; van den Maagdenberg, A.M.; Giniatullin, R.; Nistri, A.; Fabbretti, E. Familial hemiplegic migraine Cav2.1 channel mutation R192Q enhances ATP-gated P2X3 receptor activity of mouse sensory ganglion neurons mediating trigeminal pain. Mol. Pain, 2010, 6, 48.
61. Giniatullin, R.; Nistri, A.; Fabbretti, E. Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. Mol. Neurobiol., 2008, 37(1), 83-90.
62. Persson, A.K.; Xu, X. J; Wiesenfeld-Hallin, Z.; Devor, M.; Fried, K. Expression of DRG candidate pain molecules after nerve injury-a comparative study among five inbred mouse strains with contrasting pain phenotypes. J. Peripher. Nerv. Syst., 2010, 15(1), 26-39.
63. Simonetti, M.; Giniatullin, R.; Fabbretti, E. Mechanisms mediating the enhanced gene transcription of P2X3 receptor by calcitonin gene-related peptide in trigeminal sensory neurons. J. Biol. Chem., 2008, 283(27), 18743-18752.
64. Ugarte, G.D.; Opazo, T.; Leisewitz, F.; van Zundert, B.; Montecino, M. Runx1 and C/EBP transcription factors directly up-regulate P2X3 gene transcription. J. Cell. Physiol., 2012, 227(4), 1645-1652.
65. Franck, M.C.; Stenqvist, A.; Li, L.; Hao, J.; Usoskin, D.; Xu, X.; Wiesenfeld-Hallin, Z.; Ernfors, P. Essential role of Ret for defining non-peptidergic nociceptor phenotypes and functions in the adult mouse. Eur. J. Neurosci., 2011, 33(8), 1385-1400.
66. Chaumont, S.; Jiang, L.H.; Penna, A.; North, R.A.; Rassendren, F. Identification of a trafficking motif involved in the stabilization and polarization of P2X receptors. J. Biol. Chem., 2004, 279(28), 29628-29638.
67. Grote, A.; Boldogkoi, Z.; Zimmer, A.; Steinhäuser, C.; Jabs, R. Functional characterization of P2X3 receptors fused with fluorescent proteins. Mol. Membr. Biol., 2005, 22(6), 497-506.
68. Pryazhnikov, E.; Fayuk, D.; Niittykoski, M.; Giniatullin, R.; Khiroug, L. Unusually Strong Temperature Dependence of P2X3 Receptor Traffic to the Plasma Membrane. Front. Cell. Neurosci., 2011, 5, 27.
69. Vacca, F.; Giustizieri, M.; Ciotti, M.T.; Mercuri, N.B.; Volonté, C. Rapid constitutive and ligand-activated endocytic trafficking of P2X receptor. J. Neurochem., 2009, 109(4), 1031-1041.
70. Chen, X.Q.; Wang, B.; Wu, C.; Pan, J.; Yuan, B.; Su, Y.Y.; Jiang, X.Y.; Zhang, X.; Bao, L. Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons. Cell. Res., 2012, 22(4), 677-696.
71. Zhao, Q.; Logothetis, D.E.; Séguéla, P. Regulation of ATP-gated P2X receptors by phosphoinositides. Pflugers Arch., 2007, 455(1), 181-185.
72. Mo, G.; Bernier, L.P.; Zhao, Q.; Chabot-Doré, A. J; Ase, A.R.; Logothetis, D.; Cao, C.Q.; Séguéla, P. Subtype-specific regulation of P2X3 and P2X2/3 receptors by phosphoinositides in peripheral nociceptors. Mol. Pain, 2009, 5, 47.
73. Gnanasekaran, A.; Sundukova, M.; van den Maagdenberg, A.M.; Fabbretti, E.; Nistri A. Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model. Mol. Pain, 2011, 7, 77.
74. Jarvis, M.F.; Khakh, B.S. ATP-gated P2X cation-channels. Neuropharmacology, 2009, 56(1), 208-215.
75. Burnstock, G.; Kennedy, C. P2X receptors in health and disease. Adv. Pharmacol., 2011, 61, 333-372.
76. Coddou, C.; Yan, Z.; Obsil, T.; Huidobro-Toro, J.P.; Stojilkovic, S.S. Activation and regulation of purinergic P2X receptor channels. Pharmacol. Rev., 2011, 63(3), 641-683.
77. Boué-Grabot, E.; Archambault, V.; Séguéla, P. A protein kinase C site highly conserved in P2X subunits controls the desensitization kinetics of P2X2 ATP-gated channels. J. Biol. Chem., 2000, 275(14), 10190-10195.
78. Paukert, M.; Osteroth, R.; Geisler, H.S.; Brandle, U.; Glowatzki, E.; Ruppersberg, J.P.; Gründer, S. Inflammatory mediators potentiate ATP-gated channels through the P2X3 subunit. J. Biol. Chem., 2001, 276(24), 21077-21082.
79. Mo, G.; Grant, R.; O'Donnell, D.; Ragsdale, D.S.; Cao, C.Q.; Séguéla, P. Neuropathic Nav1.3-mediated sensitization to P2X activation is regulated by protein kinase C. Mol. Pain, 2011, 7, 14.
80. Brown, D.A.; Yule, D.I. Protein kinase C regulation of P2X3 receptors is unlikely to involve direct receptor phosphorylation. Biochim. Biophys. Acta, 2007, 1773(2), 166-175.
81. Cady, R.J.; Glenn, J.R.; Smith, K.M.; Durham, P.L. Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization. Mol. Pain, 2011, 7, 94.
82. Raddant, A.C.; Russo, A.F. Calcitonin gene-related peptide in migraine, intersection of peripheral inflammation and central modulation. Expert Rev. Mol. Med., 2011, 13, e36.
83. Vause, C.V.; Durham, P.L. CGRP stimulation of iNOS and NO release from trigeminal ganglion glial cells involve mitogenactivated protein kinase pathways. J. Neurochem., 2009, 110(3), 811-821.
84. Thalakoti, S.; Patil, V.V.; Damodaram, S.; Vause, C.V.; Langford, L.E.; Freeman, S.E.; Durham, P.L. Neuron-glia signaling in trigeminal ganglion, implications for migraine pathology. Headache, 2007, 47(7), 1008-1023.
85. Ceruti, S.; Villa, G.; Fumagalli, M.; Colombo, L.; Magni, G.; Zanardelli, M.; Fabbretti, E.; Verderio, C.; van den Maagdenberg, A.M.; Nistri, A.; Abbracchio, M.P. Calcitonin gene-related peptidemediated enhancement of purinergic neuron/glia communication by the algogenic factor bradykinin in mouse trigeminal ganglia from wild-type and R192Q Cav2.1 Knock-in mice, implications for basic mechanisms of migraine pain. J. Neurosci., 2011, 31(10), 3638-3649.
86. Olesen, J.; Ashina, M. Emerging migraine treatments and drug targets. Trends Pharmacol. Sci., 2011, 32(6), 352-359.
87. Coull, J.A.; Beggs, S.; Boudreau, D.; Boivin, D.; Tsuda, M.; Inoue, K.; Gravel, C.; Salter, M.W.; De Koninck, Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature, 2005, 438(7070), 1017-1021.
88. Nair, A.; Simonetti, M.; Fabbretti, E.; Nistri, A. The Cdk5 kinase downregulates ATP-gated ionotropic P2X3 receptor function via serine phosphorylation. Cell. Mol. Neurobiol., 2010, 30(4), 505-509.
89. 2+/calmodulin-dependent protein kinase II potentiates ATP responses by promoting trafficking of P2X receptors. Proc. Natl. Acad. Sci. USA, 2004, 101(32), 11868-11873.
90. Ricciotti, E.; FitzGerald, G.A. Prostaglandins and inflammation. Arterioscler. Thromb. Vasc. Biol., 2011, 31, 986-1000
91. 2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP-protein kinase A cascade. J. Physiol., 1996, 495(2), 429-440.
92. Wang, C.; Gu, Y.; Li, G.W.; Huang, L.Y. A critical role of the cAMP sensor Epac in switching protein kinase signalling in prostaglandin E2-induced potentiation of P2X3 receptor currents in inflamed rats. J. Physiol., 2007, 584(1), 191-203.
93. Oliveira, M.C.; Pelegrini-da-Silva, A.; Tambeli, C.H.; Parada, C.A. Peripheral mechanisms underlying the essential role of P2X3, P2X2/3 receptors in the development of inflammatory hyperalgesia. Pain, 2009, 141(1-2), 127-134.
94. Nistri, A.; Constanti, A. Pharmacological characterization of different types of GABA and glutamate receptors in vertebrates and invertebrates. Prog. Neurobiol., 1979, 13(2), 117-235.
95. A and cationic P2X ionotropic receptors of rat dorsal root ganglion neurons. J. Neurosci., 2001, 21(14), 4958-4968.
96. A receptors in nociceptive DRG neurons. J. Neurochem., 2007, 102(4), 1357-1368.
97. Sivilotti, L.; Nistri, A. GABA receptor mechanisms in the central nervous system. Prog. Neurobiol., 1991, 36(1), 35-92.
98. B receptor activation. Neurosci. Lett., 2003, 338(3), 181-184.
99. B receptor, a site of therapeutic benefit. Curr. Opin. Pharmacol., 2006, 6(1), 37-43
100. Eckert, W.A.; Julius, D.; Basbaum, A.I. Differential contribution of TRPV1 to thermal responses and tissue injury-induced sensitization of dorsal horn neurons in laminae I and V in the mouse. Pain, 2006, 126(1-3), 184-197.
101. Vay, L.; Gu, C.; McNaughton, P.A. The thermo-TRP ion channel family, properties and therapeutic implications. Br. J. Pharmacol., 2012, 165(4), 787-801.
102. Simonetti, M.; Fabbro, A.; D'Arco, M.; Zweyer, M.; Nistri, A.; Giniatullin, R.; Fabbretti, E. Comparison of P2X and TRPV1 receptors in ganglia or primary culture of trigeminal neurons and their modulation by NGF or serotonin. Mol. Pain, 2006, 2, 11.
103. Zhang, X.; Huang, J.; McNaughton, P.A. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J., 2005, 24(24), 4211-4223.
104. Stanchev, D.; Blosa, M.; Milius, D.; Gerevich, Z.; Rubini, P.; Schmalzing, G.; Eschrich, K.; Schaefer, M.; Wirkner, K.; Illes, P. Cross-inhibition between native and recombinant TRPV1 and P2X3 receptors. Pain, 2009, 143(1-2), 26-36.
105. Maruo, K.; Yamamoto, H.; Yamamoto, S.; Nagata, T.; Fujikawa, H.; Kanno, T.; Yaguchi, T.; Maruo, S.; Yoshiya, S.; Nishizaki, T. Modulation of P2X receptors via adrenergic pathways in rat dorsal root ganglion neurons after sciatic nerve injury. Pain, 2006, 120(1-2), 106-112.
106. Kanno, T.; Yaguchi, T.; Nishizaki, T. Noradrenaline stimulates ATP release from DRG neurons by targeting beta3 adrenoceptors as a factor of neuropathic pain. J. Cell. Physiol., 2010, 224(2), 345-351.
107. Tan, Y.; Sun, L.; Zhang, Q. Noradrenaline enhances ATP P2X3 receptor expression in dorsal root ganglion neurons of rats. Neuroscience, 2011, 176, 32-38.
108. Meisner, J.G.; Reid, A.R.; Sawynok, J. Adrenergic regulation of P2X3 and TRPV1 receptors, differential effects of spared nerve injury. Neurosci. Lett., 2008, 444(2), 172-175.
109. Nakazawa, K. ATP-activated current and its interaction with acetylcholine-activated current in rat sympathetic neurons. J. Neurosci., 1994, 14, 740-750.
110. Rogers, M.; Colquhoun, L.M.; Patrick, J.W.; Dani, J.A. Calcium flux through predominantly independent purinergic ATP and nicotinic acetylcholine receptors. J. Neurophysiol., 1997, 77(3), 1407-1417.
111. Searl, T.J.; Redman, R.S.; Silinsky, E.M. Mutual occlusion of P2X ATP receptors and nicotinic receptors on sympathetic neurons of the guinea-pig. J. Physiol., 1998, 510(3), 783-791.
112. Zhou, X.; Galligan, J.J. Non-additive interaction between nicotinic cholinergic and P2X purine receptors in guinea-pig enteric neurons in culture. J. Physiol., 1998, 513, 685-697.
113. Decker, D.A.; Galligan, J.J. Cross-inhibition between nicotinic acetylcholine receptors and P2X receptors in myenteric neurons and HEK-293 cells. Am. J. Physiol. Gastrointest. Liver Physiol., 2009, 296(6), G1267-G1276.
114. Burnstock, G. Purinergic mechanosensory transduction and visceral pain. Mol. Pain, 2009, 5, 69.
115. Abbracchio, M.P.; Burnstock, G. Purinergic signalling, pathophysiological roles. J. Pharmacol., 1998, 78(2), 113-145.
116. Villa, G.; Fumagalli, M.; Verderio, C.; Abbracchio, M.P.; Ceruti, S. Expression and contribution of satellite glial cells purinoceptors to pain transmission in sensory ganglia, an update. Neuron Glia Biol., 2010, 6(1), 31-42.
117. Toulmé, E.; Tsuda, M.; Khakh, B.S.; Inoue, K. In: Frontiers in Neuroscience. On the Role of ATP-Gated P2X Receptors in Acute, Inflammatory and Neuropathic Pain; Translational Pain Research, From Mouse to Man. In: Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press; 2010. Chapter 10. Available from: http://www.ncbi.nlm.nih.gov/bo oks/NBK57271/
118. Ceruti, S.; Fumagalli, M.; Villa, G.; Verderio, C.; Abbracchio, M.P. Purinoceptor-mediated calcium signaling in primary neuron-glia trigeminal cultures. Cell Calcium, 2008, 43(6), 576-590.
119. Ruan, H.Z.; Burnstock, G. Localisation of P2Y1 and P2Y4 receptors in dorsal root, nodose and trigeminal ganglia of the rat. Histochem. Cell Biol., 2003, 120(5), 415-426.
120. Xiang, Z.; Burnstock, G. Distribution of P2Y2 receptors in the guinea pig enteric nervous system and its coexistence with P2X2 and P2X3 receptors, neuropeptide Y, nitric oxide synthase and calretinin. Histochem. Cell Biol., 2005, 124(5), 379-390.
121. Gerevich, Z.; Zadori, Z.; Müller, C.; Wirkner, K.; Schröder, W.; Rubini, P.; Illes, P. Metabotropic P2Y receptors inhibit P2X3 receptor-channels via G protein-dependent facilitation of their desensitization. Br. J. Pharmacol., 2007, 151(2), 226-236.
122. Molliver, D.C.; Rau, K.K.; McIlwrath, S.L.; Jankowski, M.P.; Koerber, H.R. The ADP receptor P2Y1 is necessary for normal thermal sensitivity in cutaneous polymodal nociceptors. Mol. Pain, 2011, 7, 13.
123. Tsuda, M.; Tozaki-Saitoh, H.; Inoue, K. Pain and purinergic signaling. Brain Res. Rev., 2010, 63(1-2), 222-232.
124. Skaper, S.D.; Debetto, P.; Giusti, P. The P2X7 purinergic receptor: from physiology to neurological disorders. FASEB J., 2010, 24, 337-345.
125. Chen, Y.; Zhang, X.; Wang, C.; Li, G.; Gu, Y.; Huang, L.Y. Activation of P2X7 receptors in glial satellite cells reduces pain through downregulation of P2X3 receptors in nociceptive neurons. Proc. Natl. Acad. Sci. USA, 2008, 105(43), 16773-16778.
126. Chen, Y.; Li, G.; Huang, L.Y. P2X7 receptors in satellite glial cells mediate high functional expression of P2X3 receptors in immature dorsal root ganglion neurons. Mol. Pain, 2012, 8, 9.
127. Volpini, R.; Mishra, R.C.; Kachare, D.D.; Dal Ben, D.; Lambertucci, C.; Antonini, I.; Vittori, S.; Marucci, G.; Sokolova, E.; Nistri, A.; Cristalli, G. Adenine-based acyclic nucleotides as novel P2X3 receptor ligands. J. Med. Chem., 2009, 52(15), 4596-4603.
128. Cantin, L.D.; Bayrakdarian, M.; Buon, C.; Grazzini, E.; Hu, Y. J; Labrecque, J; Leung, C.; Luo, X.; Martino, G.; Paré, M.; Payza, K.; Popovic, N.; ProJean, D.; Santhakumar, V.; Walpole, C.; Yu, X.H.; Tomaszewski, M.J. Discovery of P2X3 selective antagonists for the treatment of chronic pain. Bioorg. Med. Chem. Lett., 2012, 22(7), 2565-2571.
129. 3H]A-317491, a novel high-affinity non-nucleotide antagonist that specifically labels human P2X2/3 and P2X3 receptors. J. Pharmacol. Exp. Ther., 2004, 310(1), 407-416.
130. 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. Functional downregulation of P2X3 receptor subunit in rat sensory neurons reveals a significant role in chronic neuropathic and inflammatory pain. J. Neurosci., 2002, 22(18), 8139-8147.
131. North, R.A. The P2X3 subunit: a molecular target in pain therapeutics. Curr. Opin. Investig. Drugs, 2003, 4(7), 833-840.
132. Kage, K.; Niforatos, W.; Zhu, C.Z.; Lynch, K.J.; Honore, P.; Jarvis, M.F. Alteration of dorsal root ganglion P2X3 receptor expression and function following spinal nerve ligation in the rat. Exp. Brain Res., 2002, 147(4), 511-519.
133. Xu, J.; Chu, K.L.; Brederson, J.D.; Jarvis, M.F.; McGaraughty, S. Spontaneous firing and evoked responses of spinal nociceptive neurons are attenuated by blockade of P2X3 and P2X2/3 receptors in inflamed rats. J. Neurosci. Res., 2012, 90(8), 1597-1606.
134. Wu, J.X.; Xu, M.Y.; Miao, X.R.; Lu, Z.J.; Yuan, X.M.; Li, X.Q.; Yu, W.F. Functional up-regulation of P2X3 receptors in dorsal root ganglion in a rat model of bone cancer pain. Eur. J. Pain, 2012, [Epub ahead of print].
135. Gever, J.R.; Soto, R.; Henningsen, R.A.; Martin, R.S.; Hackos, D.H.; Panicker, S.; Rubas, W.; Oglesby, I.B.; Dillon, M.P.; Milla, M.E.; Burnstock, G.; Ford, A.P. AF-353, a novel, potent and orally bioavailable P2X3/P2X2/3 receptor antagonist. Br. J. Pharmacol., 2010, 160(6), 1387-1398.
136. Kaan, T.K.; Yip, P.K.; Patel, S.; Davies, M.; Marchand, F.; Cockayne, D.A.; Nunn, P.A.; Dickenson, A.H.; Ford, A.P.; Zhong, Y.; Malcangio, M.; McMahon, S.B. Systemic blockade of P2X3 and P2X2/3 receptors attenuates bone cancer pain behaviour in rats. Brain, 2010, 133(9), 2549-2564.
137. Brotherton-Pleiss, C.E.; Dillon, M.P.; Ford, A.P.; Gever, J.R.; Carter, D.S.; Gleason, S.K.; Lin, C.J.; Moore, A.G.; Thompson, A.W.; Villa, M.; Zhai, Y. Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X3 receptor antagonist. Bioorg. Med. Chem. Lett., 2010, 20(3), 1031-1036.
138. Ballini, E.; Virginio, C.; Medhurst, S. J; Summerfield, S.G.; Aldegheri, L.; Buson, A.; Carignani, C.; Chen, Y.H.; Giacometti, A.; Lago, I.; Powell, A. J; Jarolimek, W. Characterization of three diaminopyrimidines as potent and selective antagonists of P2X3 and P2X2/3 receptors with in vivo efficacy in a pain model. Br. J. Pharmacol., 2011, 163(6), 1315-1325.
139. Grishin, E.V.; Savchenko, G.A.; Vassilevski, A.A.; Korolkova, Y.V.; Boychuk, Y.A.; Viatchenko-Karpinski, V.Y.; Nadezhdin, K.D.; Arseniev, A.S.; Pluzhnikov, K.A.; Kulyk, V.B.; Voitenko, N.V.; Krishtal, O.O. Novel peptide from spider venom inhibits P2X3 receptors and inflammatory pain. Ann. Neurol., 2010, 67(5), 680-683.
140. Jiang, L.H.; Rassendren, F.; Surprenant, A.; North, R.A. Identification of amino acid residues contributing to the ATPbinding site of a purinergic P2X receptor. J. Biol. Chem., 2000, 275(44), 34190-34196.