Sensory Nerves pp 283-332

Part of the Handbook of Experimental Pharmacology book series (HEP, volume 194)

Acid-Sensitive Ion Channels and Receptors

Chapter

Abstract

Acidosis is a noxious condition associated with inflammation, ischaemia or defective acid containment. As a consequence, acid sensing has evolved as an important property of afferent neurons with unmyelinated and thinly myelinated nerve fibres. Protons evoke multiple currents in primary afferent neurons, which are carried by several acid-sensitive ion channels. Among these, acid-sensing ion channels (ASICs) and transient receptor potential (TRP) vanilloid-1 (TRPV1) ion channels have been most thoroughly studied. ASICs survey moderate decreases in extracellular pH, whereas TRPV1 is activated only by severe acidosis resulting in pH values below 6. Two-pore-domain K+ (K2P) channels are differentially regulated by small deviations of extra- or intracellular pH from physiological levels. Other acid-sensitive channels include TRPV4, TRPC4, TRPC5, TRPP2 (PKD2L1), ionotropic purinoceptors (P2X), inward rectifier K+ channels, voltage-activated K+ channels, L-type Ca2+ channels, hyperpolarization-activated cyclic nucleotide gated channels, gap junction channels, and Cl channels. In addition, acid-sensitive G protein coupled receptors have also been identified. Most of these molecular acid sensors are expressed by primary sensory neurons, although to different degrees and in various combinations. Emerging evidence indicates that many of the acid-sensitive ion channels and receptors play a role in acid sensing, acid–induced pain and acid-evoked feedback regulation of homeostatic reactions. The existence and apparent redundancy of multiple pH surveillance systems attests to the concept that acid–base regulation is a vital issue for cell and tissue homeostasis. Since upregulation and overactivity of acid sensors appear to contribute to various forms of chronic pain, acid-sensitive ion channels and receptors are considered as targets for novel analgesic drugs. This approach will only be successful if the pathological implications of acid sensors can be differentiated pharmacologically from their physiological function.

Keywords

Acid surveillance Acid-induced pain Sour taste Acidosis Ischaemia Angina pectoris Inflammation Acid-related gastrointestinal diseases Cough Bone resorption Gastrointestinal tract Urogenital tract Pulmonary system Skin Carotid body Proton-gated currents Molecular acid sensors Acid-sensing ion channels ASIC3 TRP ion channels TRPV1 TRPP2 Two pore domain potassium channels TASK channels Proton-sensing G protein coupled receptors Ionotropic purinoceptors 

References

  1. Aihara E, Hayashi M, Sasaki Y, Kobata A, Takeuchi K (2005) Mechanisms underlying capsaicin-stimulated secretion in the stomach: comparison with mucosal acidification. J Pharmacol Exp Ther 315:423–432PubMedGoogle Scholar
  2. Akiba Y, Takeuchi T, Mizumori M, Guth PH, Engel E, Kaunitz JD (2006a) TRPV-1 knockout paradoxically protects mouse gastric mucosa from acid/ethanol-induced injury by upregulating compensatory protective mechanisms. Gastroenterology 130(Suppl 2):A–106Google Scholar
  3. Akiba Y, Ghayouri S, Takeuchi T, Mizumori M, Guth PH, Engel E, Swenson ER, Kaunitz JD (2006b) Carbonic anhydrases and mucosal vanilloid receptors help mediate the hyperemic response to luminal CO2 in rat duodenum. Gastroenterology 131:142–152PubMedGoogle Scholar
  4. Alvarez de la Rosa D, Zhang P, Shao D, White F, Canessa CM (2002) Functional implications of the localization and activity of acid-sensitive channels in rat peripheral nervous system. Proc Natl Acad Sci USA 99:2326–2331PubMedGoogle Scholar
  5. Apostolidis A, Popat R, Yiangou Y, Cockayne D, Ford AP, Davis JB, Dasgupta P, Fowler CJ, Anand P (2005) Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol 174:977–982PubMedGoogle Scholar
  6. Askwith CC, Cheng C, Ikuma M, Benson C, Price MP, Welsh MJ (2000) Neuropeptide FF and FMRFamide potentiate acid-evoked currents from sensory neurons and proton-gated DEG/ENaC channels. Neuron 26:133–141PubMedGoogle Scholar
  7. Auzanneau C, Thoreau V, Kitzis A, Becq F (2003) A novel voltage-dependent chloride current activated by extracellular acidic pH in cultured rat Sertoli cells. J Biol Chem 278:19230–19236PubMedGoogle Scholar
  8. Auzanneau C, Norez C, Antigny F, Thoreau V, Jougla C, Cantereau A, Becq F, Vandebrouck C (2008) Transient receptor potential vanilloid 1 (TRPV1) channels in cultured rat Sertoli cells regulate an acid sensing chloride channel. Biochem Pharmacol 75:476–483PubMedGoogle Scholar
  9. Avelino A, Cruz F (2006) TRPV1 (vanilloid receptor) in the urinary tract: expression, function and clinical applications. Naunyn Schmiedebergs Arch Pharmacol 373:287–299PubMedGoogle Scholar
  10. Banerjee B, Medda BK, Lazarova Z, Bansal N, Shaker R, Sengupta JN (2007) Effect of reflux-induced inflammation on transient receptor potential vanilloid one (TRPV1) expression in primary sensory neurons innervating the oesophagus of rats. Neurogastroenterol Motil 19:681–691PubMedGoogle Scholar
  11. Bang H, Kim Y, Kim D (2000) TREK-2, a new member of the mechanosensitive tandem-pore K+ channel family. J Biol Chem 275:17412–17419PubMedGoogle Scholar
  12. Baumann TK, Chaudhary P, Martenson ME (2004) Background potassium channel block and TRPV1 activation contribute to proton depolarization of sensory neurons from humans with neuropathic pain. Eur J Neurosci 19:1343–1351PubMedGoogle Scholar
  13. Bayliss DA, Talley EM, Sirois JE, Lei Q (2001) TASK-1 is a highly modulated pH-sensitive ‘leak’ K+ channel expressed in brainstem respiratory neurons. Respir Physiol 129:159–174PubMedGoogle Scholar
  14. Bearzatto B, Lesage F, Reyes R, Lazdunski M, Laduron PM (2000) Axonal transport of TREK and TRAAK potassium channels in rat sciatic nerves. Neuroreport 11:927–930PubMedGoogle Scholar
  15. Behrendt HJ, Germann T, Gillen C, Hatt H, Jostock R (2004) Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay. Br J Pharmacol 141:737–745PubMedGoogle Scholar
  16. Benson CJ, Eckert SP, McCleskey EW (1999) Acid-evoked currents in cardiac sensory neurons: a possible mediator of myocardial ischemic sensation. Circ Res 84:921–928PubMedGoogle Scholar
  17. Benson CJ, Xie J, Wemmie JA, Price MP, Henss JM, Welsh MJ, Snyder PM (2002) Heteromultimers of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons. Proc Natl Acad Sci USA 99:2338–2343PubMedGoogle Scholar
  18. Bertrand PP, Kunze WA, Bornstein JC, Furness JB, Smith ML (1997) Analysis of the responses of myenteric neurons in the small intestine to chemical stimulation of the mucosa. Am J Physiol 273:G422–G435Google Scholar
  19. Bevan S, Geppetti P (1994) Protons: small stimulants of capsaicin-sensitive sensory nerves. Trends Neurosci 17:509–512PubMedGoogle Scholar
  20. Bevan S, Yeats J (1991) Protons activate a cation conductance in a sub-population of rat dorsal root ganglion neurones. J Physiol (Lond) 433:145–161Google Scholar
  21. Bhat YM, Bielefeldt K (2006) Capsaicin receptor (TRPV1) and non-erosive reflux disease. Eur J Gastroenterol Hepatol 18:263–270PubMedGoogle Scholar
  22. Bhattacharya A, Scott BP, Nasser N, Ao H, Maher MP, Dubin AE, Swanson DM, Shankley NP, Wickenden AD, Chaplan SR (2007) Pharmacology and antitussive efficacy of 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), a transient receptor potential vanilloid 1 antagonist in guinea pigs. J Pharmacol Exp Ther 323:665–674PubMedGoogle Scholar
  23. Bielefeldt K, Davis BM (2008) Differential effects of ASIC3 and TRPV1 deletion on gastroesophageal sensation in mice. Am J Physiol 294:G130–G138Google Scholar
  24. Bina RW, Hempleman SC (2007) Evidence for TREK-like tandem-pore domain channels in intrapulmonary chemoreceptor chemotransduction. Respir Physiol Neurobiol 156:120–131PubMedGoogle Scholar
  25. Birder LA, Kanai AJ, de Groat WC, Kiss S, Nealen ML, Burke NE, Dineley KE, Watkins S, Reynolds IJ, Caterina MJ (2001) Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci USA 98:13396–13401PubMedGoogle Scholar
  26. Birder LA, Nakamura Y, Kiss S, Nealen ML, Barrick S, Kanai AJ, Wang E, Ruiz G, De Groat WC, Apodaca G, Watkins S, Caterina MJ (2002) Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci 5:856–860PubMedGoogle Scholar
  27. Bley KR (2004) Recent developments in transient receptor potential vanilloid receptor 1 agonist-based therapies. Expert Opin Investig Drugs 13:1445–1456PubMedGoogle Scholar
  28. Brady CM, Apostolidis AN, Harper M, Yiangou Y, Beckett A, Jacques TS, Freeman A, Scaravilli F, Fowler CJ, Anand P (2004) Parallel changes in bladder suburothelial vanilloid receptor TRPV1 and pan-neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor overactivity after intravesical resiniferatoxin treatment. BJU Int 93:770–776PubMedGoogle Scholar
  29. Breese NM, George AC, Pauers LE, Stucky CL (2005) Peripheral inflammation selectively increases TRPV1 function in IB4-positive sensory neurons from adult mouse. Pain 115:37–49PubMedGoogle Scholar
  30. Brown SG, Townsend-Nicholson A, Jacobson KA, Burnstock G, King BF (2002) Heteromultimeric P2X1/2 receptors show a novel sensitivity to extracellular pH. J Pharmacol Exp Ther 300:673–680PubMedGoogle Scholar
  31. Buckler KJ (2007) TASK-like potassium channels and oxygen sensing in the carotid body. Respir Physiol Neurobiol 157:55–64PubMedGoogle Scholar
  32. Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87:659–797PubMedGoogle Scholar
  33. Cadiou H, Studer M, Jones NG, Smith ES, Ballard A, McMahon SB, McNaughton PA (2007) Modulation of acid-sensing ion channel activity by nitric oxide. J Neurosci 27:13251–13260PubMedGoogle Scholar
  34. Campanucci VA, Fearon IM, Nurse CA (2003) A novel O2-sensing mechanism in rat glossopharyngeal neurones mediated by a halothane-inhibitable background K+ conductance. J Physiol (Lond) 548:731–743Google Scholar
  35. Canning BJ, Farmer DG, Mori N (2006) Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs. Am J Physiol 291:R454–R463Google Scholar
  36. Carlton SM, Coggeshall RE (2001) Peripheral capsaicin receptors increase in the inflamed rat hindpaw: a possible mechanism for peripheral sensitization. Neurosci Lett 310:53–56PubMedGoogle Scholar
  37. Catarsi S, Babinski K, Séguéla P (2001) Selective modulation of heteromeric ASIC proton-gated channels by neuropeptide FF. Neuropharmacology 41:592–600PubMedGoogle Scholar
  38. Caterina MJ, Julius D (2001) The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci 24:487–517PubMedGoogle Scholar
  39. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824PubMedGoogle Scholar
  40. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313PubMedGoogle Scholar
  41. Chan CL, Facer P, Davis JB, Smith GD, Egerton J, Bountra C, Williams NS, Anand P (2003) Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet 361:385–391PubMedGoogle Scholar
  42. Chandrashekar J, Hoon MA, Ryba NJ, Zuker CS (2006) The receptors and cells for mammalian taste. Nature 444:288–294PubMedGoogle Scholar
  43. Chapman CG, Meadows HJ, Godden RJ, Campbell DA, Duckworth M, Kelsell RE, Murdock PR, Randall AD, Rennie GI, Gloger IS (2000) Cloning, localisation and functional expression of a novel human, cerebellum specific, two pore domain potassium channel. Mol Brain Res 82:74–83PubMedGoogle Scholar
  44. Chavez RA, Gray AT, Zhao BB, Kindler CH, Mazurek MJ, Mehta Y, Forsayeth JR, Yost CS (1999) TWIK-2, a new weak inward rectifying member of the tandem pore domain potassium channel family. J Biol Chem 274:7887–7892PubMedGoogle Scholar
  45. Chen CC, England S, Akopian AN, Wood JN (1998) A sensory neuron-specific, proton-gated ion channel. Proc Natl Acad Sci USA 95:10240–10245PubMedGoogle Scholar
  46. Chen CC, Zimmer A, Sun WH, Hall J, Brownstein MJ, Zimmer A (2002) A role for ASIC3 in the modulation of high-intensity pain stimuli. Proc Natl Acad Sci USA 99:8992–8997PubMedGoogle Scholar
  47. Chizh BA, Illes P (2001) P2X receptors and nociception. Pharmacol Rev 53:553–568PubMedGoogle Scholar
  48. Chuang YC, Chancellor MB, Seki S, Yoshimura N, Tyagi P, Huang L, Lavelle JP, De Groat WC, Fraser MO (2003) Intravesical protamine sulfate and potassium chloride as a model for bladder hyperactivity. Urology 61:664–670PubMedGoogle Scholar
  49. Chuang YC, Yoshimura N, Huang CC, Chiang PH, Chancellor MB (2004) Intravesical botulinum toxin a administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol 172:1529–1532PubMedGoogle Scholar
  50. Clapham DE, Julius D, Montell C, Schultz G (2005) International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels. Pharmacol Rev 57:427–450PubMedGoogle Scholar
  51. Clarke GD, Davison JS (1978) Mucosal receptors in the gastric antrum and small intestine of the rat with afferent fibres in the cervical vagus. J Physiol (Lond) 284:55–67Google Scholar
  52. Clarke CE, Benham CD, Bridges A, George AR, Meadows HJ (2000) Mutation of histidine 286 of the human P2X4 purinoceptor removes extracellular pH sensitivity. J Physiol (Lond) 523:697–703Google Scholar
  53. Claydon TW, Boyett MR, Sivaprasadarao A, Orchard CH (2000) Two pore residues mediate acidosis-induced enhancement of C-type inactivation of the Kv1.4 K+ channel. Am J Physiol 283:C1114–C1121Google Scholar
  54. Clyne JD, LaPointe LD, Hume RI (2002) The role of histidine residues in modulation of the rat P2X2 purinoceptor by zinc and pH. J Physiol (Lond) 539:347–359Google Scholar
  55. Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, Malmberg AB, Cain G, Berson A, Kassotakis L, Hedley L, Lachnit WG, Burnstock G, McMahon SB, Ford AP (2000) Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407:1011–1015PubMedGoogle Scholar
  56. 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 (2005) 567:621–639Google Scholar
  57. Coffin B, Chollet R, Flourie B, Lemann M, Franchisseur C, Rambaud JC, Jian R (2001) Intraluminal modulation of gastric sensitivity to distension: effects of hydrochloric acid and meal. Am J Physiol 280:G904–G909Google Scholar
  58. Cooper BY, Johnson RD, Rau KK (2004) Characterization and function of TWIK-related acid sensing K+ channels in a rat nociceptive cell. Neuroscience 129:209–224PubMedGoogle Scholar
  59. Cruz F, Dinis P (2007) Resiniferatoxin and botulinum toxin type A for treatment of lower urinary tract symptoms. Neurourol Urodyn 26(6 suppl):920–927PubMedGoogle Scholar
  60. Daly D, Rong W, Chess-Williams R, Chapple C, Grundy D (2007) Bladder afferent sensitivity in wild-type and TRPV1 knockout mice. J Physiol (Lond) 583:663–674Google Scholar
  61. Dang K, Bielefeldt K, Gebhart GF (2005) Differential responses of bladder lumbosacral and thoracolumbar dorsal root ganglion neurons to purinergic agonists, protons, and capsaicin. J Neurosci 25:3973–3984PubMedGoogle Scholar
  62. Danzer M, Jocic M, Samberger C, Painsipp E, Bock E, Pabst MA, Crailsheim K, Schicho R, Lippe IT, Holzer P (2004) Stomach-brain communication by vagal afferents in response to luminal acid backdiffusion, gastrin, and gastric acid secretion. Am J Physiol 286:G403–G411Google Scholar
  63. Davies NW, Lux HD, Morad M (1988) Site and mechanism of activation of proton-induced sodium current in chick dorsal root ganglion neurones. J Physiol (Lond) 400:159–187Google Scholar
  64. Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers DC, Bingham S, Randall A, Sheardown SA (2000) Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405:183–187PubMedGoogle Scholar
  65. Delmas P (2005) Polycystins: polymodal receptor/ion-channel cellular sensors. Pflügers Arch 451:264–276PubMedGoogle Scholar
  66. Dean JB, Ballantyne D, Cardone DL, Erlichman JS, Solomon IC (2002) Role of gap junctions in CO2 chemoreception and respiratory control. Am J Physiol 283:L665–L670Google Scholar
  67. Decher N, Maier M, Dittrich W, Gassenhuber J, Bruggemann A, Busch AE, Steinmeyer K (2001) Characterization of TASK-4, a novel member of the pH-sensitive, two-pore domain potassium channel family. FEBS Lett 492:84–89PubMedGoogle Scholar
  68. Deval E, Baron A, Lingueglia E, Mazarguil H, Zajac JM, Lazdunski M (2003) Effects of neuropeptide SF and related peptides on acid sensing ion channel 3 and sensory neuron excitability. Neuropharmacology 44:662–671PubMedGoogle Scholar
  69. Ding S, Sachs F (1999) Single channel properties of P2X2 purinoceptors. J Gen Physiol 113:695–720PubMedGoogle Scholar
  70. Diochot S, Baron A, Rash LD, Deval E, Escoubas P, Scarzello S, Salinas M, Lazdunski M (2004) A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J 23:1516–1525PubMedGoogle Scholar
  71. Diochot S, Salinas M, Baron A, Escoubas P, Lazdunski M (2007) Peptides inhibitors of acid-sensing ion channels. Toxicon 49:271–284PubMedGoogle Scholar
  72. Dobler T, Springauf A, Tovornik S, Weber M, Schmitt A, Sedlmeier R, Wischmeyer E, Döring F (2007) TRESK two-pore-domain K+ channels constitute a significant component of background potassium currents in murine dorsal root ganglion neurones. J Physiol (Lond) 585:867–879Google Scholar
  73. Docherty RJ, Yeats JC, Piper AS (1997) Capsazepine block of voltage-activated calcium channels in adult rat dorsal root ganglion neurones in culture. Br J Pharmacol 121:1461–1467PubMedGoogle Scholar
  74. Drewes AM, Schipper KP, Dimcevski G, Petersen P, Gregersen H, Funch-Jensen P, Arendt-Nielsen L (2003) Gut pain and hyperalgesia induced by capsaicin: a human experimental model. Pain 104:333–341PubMedGoogle Scholar
  75. Duan B, Wu LJ, Yu YQ, Ding Y, Jing L, Xu L, Chen J, Xu TL (2007) Upregulation of acid-sensing ion channel ASIC1a in spinal dorsal horn neurons contributes to inflammatory pain hypersensitivity. J Neurosci 27:11139–11148PubMedGoogle Scholar
  76. Dubé GR, Lehto SG, Breese NM, Baker SJ, Wang X, Matulenko MA, Honoré P, Stewart AO, Moreland RB, Brioni JD (2005) Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels. Pain 117:88–96PubMedGoogle Scholar
  77. Dunn PM, Zhong Y, Burnstock G (2001) P2X receptors in peripheral neurons. Prog Neurobiol 65:107–134PubMedGoogle Scholar
  78. Duprat F, Lesage F, Fink M, Reyes R, Heurteaux C, Lazdunski M (1997) TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J 16:5464–5471PubMedGoogle Scholar
  79. Duprat F, Girard C, Jarretou G, Lazdunski M (2005) Pancreatic two P domain K+ channels TALK-1 and TALK-2 are activated by nitric oxide and reactive oxygen species. J Physiol (Lond) 562:235–244Google Scholar
  80. Duprat F, Lauritzen I, Patel A, Honoré E (2007) The TASK background K2P channels: chemo- and nutrient sensors. Trends Neurosci 30:573–580PubMedGoogle Scholar
  81. Escoubas P, De Weille JR, Lecoq A, Diochot S, Waldmann R, Champigny G, Moinier D, Menez A, Lazdunski M (2000) Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J Biol Chem 275:25116–25121PubMedGoogle Scholar
  82. Faisy C, Planquette B, Naline E, Risse PA, Frossard N, Fagon JY, Advenier C, Devillier P (2007) Acid-induced modulation of airway basal tone and contractility: role of acid-sensing ion channels (ASICs) and TRPV1 receptor. Life Sci 81:1094–1102PubMedGoogle Scholar
  83. Fallingborg J (1999) Intraluminal pH of the human gastrointestinal tract. Dan Med Bull 46:183–196PubMedGoogle Scholar
  84. Filosa JA, Putnam RW (2003) Multiple targets of chemosensitive signaling in locus coeruleus neurons: role of K+ and Ca2+ channels. Am J Physiol 284:C145–C155Google Scholar
  85. Fischer MJ, Reeh PW, Sauer SK (2003) Proton-induced calcitonin gene-related peptide release from rat sciatic nerve axons, in vitro, involving TRPV1. Eur J Neurosci 18:803–810PubMedGoogle Scholar
  86. Forster ER, Green T, Elliot M, Bremner A, Dockray GJ (1990) Gastric emptying in rats: role of afferent neurons and cholecystokinin. Am J Physiol 258:G552–G556PubMedGoogle Scholar
  87. Friese MA, Craner MJ, Etzensperger R, Vergo S, Wemmie JA, Welsh MJ, Vincent A, Fugger L (2007) Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat Med 13:1483–1489PubMedGoogle Scholar
  88. Fujino K, de la Fuente SG, Takami Y, Takahashi T, Mantyh CR (2006) Attenuation of acid induced oesophagitis in VR-1 deficient mice. Gut 55:34–40PubMedGoogle Scholar
  89. Fukuda T, Ichikawa H, Terayama R, Yamaai T, Kuboki T, Sugimoto T (2006) ASIC3-immunoreactive neurons in the rat vagal and glossopharyngeal sensory ganglia. Brain Res 1081:150–155PubMedGoogle Scholar
  90. Gabriel A, Abdallah M, Yost CS, Winegar BD, Kindler CH (2002) Localization of the tandem pore domain K+ channel KCNK5 (TASK-2) in the rat central nervous system. Mol Brain Res 98:153–163PubMedGoogle Scholar
  91. Gao Z, Henig O, Kehoe V, Sinoway LI, Li J (2006) Vanilloid type 1 receptor and the acid-sensing ion channel mediate acid phosphate activation of muscle afferent nerves in rats. J Appl Physiol 100:421–426PubMedGoogle Scholar
  92. Gao Z, Li JD, Sinoway LI, Li J (2007a) Effect of muscle interstitial pH on P2X and TRPV1 receptor-mediated pressor response. J Appl Physiol 102:2288–2293PubMedGoogle Scholar
  93. Gao Y, Liu SS, Qiu S, Cheng W, Zheng J, Luo JH (2007b) Fluorescence resonance energy transfer analysis of subunit assembly of the ASIC channel. Biochem Biophys Res Commun 359:143–150PubMedGoogle Scholar
  94. García-Martínez C, Fernández-Carvajal A, Valenzuela B, Gomis A, Van Den Nest W, Ferroni S, Carreño C, Belmonte C, Ferrer-Montiel A (2006) Design and characterization of a noncompetitive antagonist of the transient receptor potential vanilloid subunit 1 channel with in vivo analgesic and anti-inflammatory activity. J Pain 7:735–746PubMedGoogle Scholar
  95. García-Sanz N, Fernández-Carvajal A, Morenilla-Palao C, Planells-Cases R, Fajardo-Sánchez E, Fernández-Ballester G, Ferrer-Montiel A (2004) Identification of a tetramerization domain in the C terminus of the vanilloid receptor. J Neurosci 24:5307–5314PubMedGoogle Scholar
  96. Gavva NR, Klionsky L, Qu Y, Shi L, Tamir R, Edenson S, Zhang TJ, Viswanadhan VN, Toth A, Pearce LV, Vanderah TW, Porreca F, Blumberg PM, Lile J, Sun Y, Wild K, Louis JC, Treanor JJ (2004) Molecular determinants of vanilloid sensitivity in TRPV1. J Biol Chem 279:20283–20295PubMedGoogle Scholar
  97. Gavva NR, Tamir R, Klionsky L, Norman MH, Louis JC, Wild KD, Treanor JJ (2005a) Proton activation does not alter antagonist interaction with the capsaicin-binding pocket of TRPV1. Mol Pharmacol 68:1524–1533PubMedGoogle Scholar
  98. Gavva NR, Tamir R, Qu Y, Klionsky L, Zhang TJ, Immke D, Wang J, Zhu D, Vanderah TW, Porreca F, Doherty EM, Norman MH, Wild KD, Bannon AW, Louis JC, Treanor JJ (2005b) AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties. J Pharmacol Exp Ther 313:474–484PubMedGoogle Scholar
  99. Gavva NR, Bannon AW, Surapaneni S, Hovland DN Jr, Lehto SG, Gore A, Juan T, Deng H, Han B, Klionsky L, Kuang R, Le A, Tamir R, Wang J, Youngblood B, Zhu D, Norman MH, Magal E, Treanor JJ, Louis JC (2007) The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation. J Neurosci 27:3366–3374PubMedGoogle Scholar
  100. Gavva NR, Treanor JJ, Garami A, Fang L, Surapaneni S, Akrami A, Alvarez F, Bak A, Darling M, Gore A, Jang GR, Kesslak JP, Ni L, Norman MH, Palluconi G, Rose MJ, Salfi M, Tan E, Romanovsky AA, Banfield C, Davar G (2008) Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136:202–210PubMedGoogle Scholar
  101. Geppetti P, Tramontana M, Evangelista S, Renzi D, Maggi CA, Fusco BM, Del Bianco E (1991) Differential effect on neuropeptide release of different concentrations of hydrogen ions on afferent and intrinsic neurons of the rat stomach. Gastroenterology 101:1505–1511PubMedGoogle Scholar
  102. Gerevich Z, Zadori ZS, Köles L, Kopp L, Milius D, Wirkner K, Gyires K, Illes P (2007) Dual effect of acid pH on purinergic P2X3 receptors depends on the histidine 206 residue. J Biol Chem 282:33949–33957PubMedGoogle Scholar
  103. Gharat LA, Szallasi A (2008) Advances in the design and therapeutic use of capsaicin receptor TRPV1 agonists and antagonists. Expert Opin Ther Patents 18:159–209Google Scholar
  104. Ghilardi JR, Röhrich H, Lindsay TH, Sevcik MA, Schwei MJ, Kubota K, Halvorson KG, Poblete J, Chaplan SR, Dubin AE, Carruthers NI, Swanson D, Kuskowski M, Flores CM, Julius D, Mantyh PW (2005) Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain. J Neurosci 25:3126–3131PubMedGoogle Scholar
  105. Girard C, Duprat F, Terrenoire C, Tinel N, Fosset M, Romey G, Lazdunski M, Lesage F (2001) Genomic and functional characteristics of novel human pancreatic 2P domain K+ channels. Biochem Biophys Res Commun 282:249–256PubMedGoogle Scholar
  106. Goldstein SA, Bockenhauer D, O'Kelly I, Zilberberg N (2001) Potassium leak channels and the KCNK family of two-P-domain subunits. Nat Rev Neurosci 2:175–184PubMedGoogle Scholar
  107. Goldstein SA, Bayliss DA, Kim D, Lesage F, Plant LD, Rajan S (2005) International Union of Pharmacology. LV. Nomenclature and molecular relationships of two-P potassium channels. Pharmacol Rev 57:527–540PubMedGoogle Scholar
  108. Goodis HE, Poon A, Hargreaves KM (2006) Tissue pH and temperature regulate pulpal nociceptors. J Dent Res 85:1046–1049PubMedGoogle Scholar
  109. Groth M, Helbig T, Grau V, Kummer W, Haberberger RV (2006) Spinal afferent neurons projecting to the rat lung and pleura express acid sensitive channels. Respir Res 7:96PubMedGoogle Scholar
  110. Gu Q, Lee LY (2006) Characterization of acid signaling in rat vagal pulmonary sensory neurons. Am J Physiol 291:L58–L65Google Scholar
  111. Gu W, Schlichthörl G, Hirsch JR, Engels H, Karschin C, Karschin A, Derst C, Steinlein OK, Daut J (2002) Expression pattern and functional characteristics of two novel splice variants of the two-pore-domain potassium channel TREK-2. J Physiol (Lond) 539:657–668Google Scholar
  112. Güler AD, Lee H, Iida T, Shimizu I, Tominaga M, Caterina M (2002) Heat-evoked activation of the ion channel, TRPV4. J Neurosci 22:6408–6414PubMedGoogle Scholar
  113. Gunthorpe MJ, Benham CD, Randall A, Davis JB (2002) The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Pharmacol Sci 23:183–191PubMedGoogle Scholar
  114. Gunthorpe MJ, Rami HK, Jerman JC, Smart D, Gill CH, Soffin EM, Luis Hannan S, Lappin SC, Egerton J, Smith GD, Worby A, Howett L, Owen D, Nasir S, Davies CH, Thompson M, Wyman PA, Randall AD, Davis JB (2004) Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist. Neuropharmacology 46:133–149PubMedGoogle Scholar
  115. Guo A, Vulchanova L, Wang J, Li X, Elde R (1999) Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur J Neurosci 11:946–958PubMedGoogle Scholar
  116. Hamilton SG, McMahon SB, Lewin GR (2001) Selective activation of nociceptors by P2X receptor agonists in normal and inflamed rat skin. J Physiol (Lond) 534:437–445Google Scholar
  117. Han J, Kang D, Kim D (2003) Functional properties of four splice variants of a human pancreatic tandem-pore K+ channel, TALK-1. Am J Physiol 285:C529–C538Google Scholar
  118. Hayes SG, Kindig AE, Kaufman MP (2007) Blockade of acid sensing ion channels attenuates the exercise pressor reflex in cats. J Physiol 581:1271–1282PubMedGoogle Scholar
  119. Hellwig N, Plant TD, Janson W, Schäfer M, Schultz G, Schaefer M (2004) TRPV1 acts as proton channel to induce acidification in nociceptive neurons. J Biol Chem 279:34553–34561PubMedGoogle Scholar
  120. Hervieu GJ, Cluderay JE, Gray CW, Green PJ, Ranson JL, Randall AD, Meadows HJ (2001) Distribution and expression of TREK-1, a two-pore-domain potassium channel, in the adult rat CNS. Neuroscience 103:899–919PubMedGoogle Scholar
  121. Hicks GA (2006) TRP channels as therapeutic targets: hot property, or time to cool down? Neurogastroenterol Motil 18:590–594PubMedGoogle Scholar
  122. Hoheisel U, Reinöhl J, Unger T, Mense S (2004) Acidic pH and capsaicin activate mechanosensitive group IV muscle receptors in the rat. Pain 110:149–157PubMedGoogle Scholar
  123. Holzer P (1988) Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides Neuroscience 24:739–768PubMedGoogle Scholar
  124. Holzer P (1991) Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 43:143–201PubMedGoogle Scholar
  125. Holzer P (1998) Neural emergency system in the stomach. Gastroenterology 114:823–839PubMedGoogle Scholar
  126. Holzer P (2003) Acid-sensitive ion channels in gastrointestinal function. Curr Opin Pharmacol 3:618–625PubMedGoogle Scholar
  127. Holzer P (2004a) TRPV1 and the gut: from a tasty receptor for a painful vanilloid to a key player in hyperalgesia. Eur J Pharmacol 500:231–241PubMedGoogle Scholar
  128. Holzer P (2004b) Vanilloid receptor TRPV1: hot on the tongue and inflaming the colon. Neurogastroenterol Motil 16:697–699PubMedGoogle Scholar
  129. Holzer P (2007) Taste receptors in the gastrointestinal tract. V. Acid sensing in the gastrointestinal tract. Am J Physiol 292:G699–G705Google Scholar
  130. Holzer P, Maggi CA (1998) Dissociation of dorsal root ganglion neurons into afferent and efferent-like neurons. Neuroscience 86:389–398PubMedGoogle Scholar
  131. Holzer P, Painsipp E, Jocic M, Heinemann A (2003) Acid challenge delays gastric pressure adaptation, blocks gastric emptying and stimulates gastric fluid secretion in the rat. Neurogastroenterol Motil 15:45–55PubMedGoogle Scholar
  132. Holzer P, Wultsch T, Edelsbrunner M, Mitrovic M, Shahbazian A, Painsipp E, Bock E, Pabst MA (2007) Increase in gastric acid-induced afferent input to the brainstem in mice with gastritis. Neuroscience 145:1108–1119PubMedGoogle Scholar
  133. Honore P, Luger NM, Sabino MA, Schwei MJ, Rogers SD, Mach DB, O'Keefe PF, Ramnaraine ML, Clohisy DR, Mantyh PW (2000) Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med 6:521–528PubMedGoogle Scholar
  134. Honore P, Mikusa J, Bianchi B, McDonald H, Cartmell J, Faltynek C, Jarvis MF (2002) TNP-ATP, a potent P2X3 receptor antagonist, blocks acetic acid-induced abdominal constriction in mice: comparison with reference analgesics. Pain 96:99–105PubMedGoogle Scholar
  135. Honoré E, Maingret F, Lazdunski M, Patel AJ (2002) An intracellular proton sensor commands lipid- and mechano-gating of the K+ channel TREK-1. EMBO J 21:2968–2976PubMedGoogle Scholar
  136. Huang AL, Chen X, Hoon MA, Chandrashekar J, Guo W, Tränkner D, Ryba NJ, Zuker CS (2006) The cells and logic for mammalian sour taste detection. Nature 442:934–938PubMedGoogle Scholar
  137. Huang CW, Tzeng JN, Chen YJ, Tsai WF, Chen CC, Sun WH (2007) Nociceptors of dorsal root ganglion express proton-sensing G-protein-coupled receptors. Mol Cell Neurosci 36:195–210PubMedGoogle Scholar
  138. Hughes PA, Brierley SM, Young RL, Blackshaw LA (2007) Localization and comparative analysis of acid-sensing ion channel (ASIC1, 2, and 3) mRNA expression in mouse colonic sensory neurons within thoracolumbar dorsal root ganglia. J Comp Neurol 500:863–875PubMedGoogle Scholar
  139. Hunt J (2006) Exhaled breath condensate pH: reflecting acidification of the airway at all levels. Am J Respir Crit Care Med 173:366–367PubMedGoogle Scholar
  140. Ikeda Y, Ueno A, Naraba H, Oh-ishi S (2001) Involvement of vanilloid receptor VR1 and prostanoids in the acid-induced writhing responses of mice. Life Sci 69:2911–2919PubMedGoogle Scholar
  141. Immke DC, McCleskey EW (2001) Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nat Neurosci 4:869–870PubMedGoogle Scholar
  142. Immke DC, McCleskey EW (2003) Protons open acid-sensing ion channels by catalyzing relief of Ca2+ blockade. Neuron 37:75–84PubMedGoogle Scholar
  143. Ishimaru Y, Inada H, Kubota M, Zhuang H, Tominaga M, Matsunami H (2006) Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor. Proc Natl Acad Sci USA 103:12569–12574PubMedGoogle Scholar
  144. Jahr H, van Driel M, van Osch GJ, Weinans H, van Leeuwen JP (2005) Identification of acid-sensing ion channels in bone. Biochem Biophys Res Commun 337:349–354PubMedGoogle Scholar
  145. Jancsó N (1960) Role of the nerve terminals in the mechanism of inflammatory reactions. Bull Millard Fillmore Hosp 7:53–77Google Scholar
  146. Jarvis MF, Burgard EC, McGaraughty S, Honore P, Lynch K, Brennan TJ, Subieta A, Van Biesen T, Cartmell J, Bianchi B, Niforatos W, Kage K, Yu H, Mikusa J, Wismer CT, Zhu CZ, Chu K, Lee CH, Stewart AO, Polakowski J, Cox BF, Kowaluk E, Williams M, Sullivan J, Faltynek C (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 USA 99:17179–17184PubMedGoogle Scholar
  147. Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ (2002) p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36:57–68PubMedGoogle Scholar
  148. Jia Y, Lee LY (2007) Role of TRPV receptors in respiratory diseases. Biochim Biophys Acta 1772:915–927PubMedGoogle Scholar
  149. Jiang M, Dun W, Tseng GN (1999) Mechanism for the effects of extracellular acidification on HERG-channel function. Am J Physiol 277:H1283–H1292PubMedGoogle Scholar
  150. Jiang C, Rojas A, Wang R, Wang X (2005) CO2 central chemosensitivity: why are there so many sensing molecules? Respir Physiol Neurobiol 145:115–126PubMedGoogle Scholar
  151. Jiang N, Rau KK, Johnson RD, Cooper BY (2006) Proton sensitivity Ca2+ permeability and molecular basis of acid-sensing ion channels expressed in glabrous and hairy skin afferents. J Neurophysiol 95:2466–2478PubMedGoogle Scholar
  152. Jones NG, Slater R, Cadiou H, McNaughton P, McMahon SB (2004) Acid-induced pain and its modulation in humans. J Neurosci 24:10974–10979PubMedGoogle Scholar
  153. Jordt SE, Tominaga M, Julius D (2000) Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc Natl Acad Sci USA 97:8134–8139PubMedGoogle Scholar
  154. Kagawa S, Aoi M, Kubo Y, Kotani T, and Takeuchi K (2003) Stimulation by capsaicin of duodenal HCO3 secretion via afferent neurons and vanilloid receptors in rats: comparison with acid-induced HCO3 response. Dig Dis Sci 48:1850–1856PubMedGoogle Scholar
  155. Kang D, Kim D (2004) Single-channel properties and pH sensitivity of two-pore domain K+ channels of the TALK family. Biochem Biophys Res Commun 315:836–844PubMedGoogle Scholar
  156. Kang D, Kim D (2006) TREK-2 (K2P10.1) and TRESK (K2P18.1) are major background K+ channels in dorsal root ganglion neurons. Am J Physiol 291:C138–C146Google Scholar
  157. Kang JY, Yap I (1991) Acid and gastric ulcer pain. J Clin Gastroenterol 13:514–516PubMedGoogle Scholar
  158. Kataoka S, Yang R, Ishimaru Y, Matsunami H, Sévigny J, Kinnamon JC, Finger TE (2008) The candidate sour taste receptor, PKD2L1, is expressed by type III taste cells in the mouse. Chem Senses 33:243–254PubMedGoogle Scholar
  159. Kellenberger S, Schild L (2002) Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol Rev 82:735–767PubMedGoogle Scholar
  160. Kim Y, Bang H, Kim D (2000) TASK-3, a new member of the tandem pore K+ channel family. J Biol Chem 275:9340–9347PubMedGoogle Scholar
  161. Kim Y, Gnatenco C, Bang H, Kim D (2001a) Localization of TREK-2 K+ channel domains that regulate channel kinetics and sensitivity to pressure, fatty acids and pHi. Pflügers Arch 442:952–960PubMedGoogle Scholar
  162. Kim Y, Bang H, Gnatenco C, Kim D (2001b) Synergistic interaction and the role of C-terminus in the activation of TRAAK K+ channels by pressure, free fatty acids and alkali. Pflügers Arch 442:64–72PubMedGoogle Scholar
  163. 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 20:4871–4877PubMedGoogle Scholar
  164. Kollarik M, Undem BJ (2002) Mechanisms of acid-induced activation of airway afferent nerve fibres in guinea-pig. J Physiol 543:591–600PubMedGoogle Scholar
  165. Kollarik M, Fei Ru F, Undem BJ (2007) Acid-sensitive vagal sensory pathways and cough. Pulm Pharmacol Ther 20:402–411PubMedGoogle Scholar
  166. Konnerth A, Lux HD, Morad M (1987) Proton-induced transformation of calcium channel in chick dorsal root ganglion cells. J Physiol (Lond) 386:603–633Google Scholar
  167. Kress M, Waldmann R (2006) Acid sensing ionic channels. Curr Top Membr 57:241–276Google Scholar
  168. Krishek BJ, Smart TG (2001) Proton sensitivity of rat cerebellar granule cell GABAA receptors: dependence on neuronal development. J Physiol (Lond) 530:219–233Google Scholar
  169. Krishtal O (2003) The ASICs: signaling molecules? Modulators? Trends Neurosci 26:477–483PubMedGoogle Scholar
  170. Krishtal OA, Pidoplichko VI (1981) A receptor for protons in the membrane of sensory neurons may participate in nociception. Neuroscience 6:2599–2601PubMedGoogle Scholar
  171. Lamb K, Kang YM, Gebhart GF, Bielefeldt K (2003) Gastric inflammation triggers hypersensitivity to acid in awake rats. Gastroenterology 125:1410–1418PubMedGoogle Scholar
  172. Leffler A, Mönter B, Koltzenburg M (2006) The role of the capsaicin receptor TRPV1 and acid-sensing ion channels ASICs in proton sensitivity of subpopulations of primary nociceptive neurons in rats and mice. Neuroscience 139:699–709PubMedGoogle Scholar
  173. Lehto SG, Tamir R, Deng H, Klionsky L, Kuang R, Le A, Lee D, Louis JC, Magal E, Manning BH, Rubino J, Surapaneni S, Tamayo N, Wang T, Wang J, Wang J, Wang W, Youngblood B, Zhang M, Zhu D, Norman MH, Gavva NR (2008) Antihyperalgesic effects of AMG8562, a novel vanilloid receptor TRPV1 modulator that does not cause hyperthermia in rats. J Pharmacol Exp Ther 326:218–229PubMedGoogle Scholar
  174. Lesage F, Lazdunski M (2000) Molecular and functional properties of two-pore-domain potassium channels. Am J Physiol 279:F793–F801Google Scholar
  175. Lesage F, Terrenoire C, Romey G, Lazdunski M (2000) Human TREK2, a 2P domain mechano-sensitive K+ channel with multiple regulations by polyunsaturated fatty acids, lysophospholipids, and Gs, Gi, and Gq protein-coupled receptors. J Biol Chem 275:28398–28405PubMedGoogle Scholar
  176. Leung SY, Niimi A, Williams AS, Nath P, Blanc FX, Dinh QT, Chung KF (2007) Inhibition of citric acid- and capsaicin-induced cough by novel TRPV-1 antagonist, V112220, in guinea-pig. Cough 3:10PubMedGoogle Scholar
  177. Li C, Peoples RW, Weight FF (1996) Proton potentiation of ATP-gated ion channel responses to ATP and Zn2+ in rat nodose ganglion neurons. J Neurophysiol 76:3048–3058PubMedGoogle Scholar
  178. Li C, Peoples RW, Weight FF (1997) Enhancement of ATP-activated current by protons in dorsal root ganglion neurons. Pflügers Arch 433:446–454PubMedGoogle Scholar
  179. Li J, Maile MD, Sinoway AN, Sinoway LI (2004) Muscle pressor reflex: potential role of vanilloid type 1 receptor and acid-sensing ion channel. J Appl Physiol 97:1709–1714PubMedGoogle Scholar
  180. Lin W, Burks CA, Hansen DR, Kinnamon SC, Gilbertson TA (2004) Taste receptor cells express pH-sensitive leak K+ channels. J Neurophysiol 92:2909–2919PubMedGoogle Scholar
  181. Lingueglia E (2007) Acid-sensing ion channels in sensory perception. J Biol Chem 282:17325–17329PubMedGoogle Scholar
  182. Lingueglia E, de Weille JR, Bassilana F, Heurteaux C, Sakai H, Waldmann R, Lazdunski M (1997) A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells. J Biol Chem 272:29778–29783PubMedGoogle Scholar
  183. Liu L, Simon SA (1997) Capsazepine, a vanilloid receptor antagonist, inhibits nicotinic acetylcholine receptors in rat trigeminal ganglia. Neurosci Lett 228:29–32PubMedGoogle Scholar
  184. Liu M, King BF, Dunn PM, Rong W, Townsend-Nicholson A, Burnstock G (2001) Coexpression of P2X3 and P2X2 receptor subunits in varying amounts generates heterogeneous populations of P2X receptors that evoke a spectrum of agonist responses comparable to that seen in sensory neurons. J Pharmacol Exp Ther 296:1043–1050PubMedGoogle Scholar
  185. Liu M, Willmott NJ, Michael GJ, Priestley JV (2004) Differential pH and capsaicin responses of Griffonia simplicifolia IB4 (IB4)-positive and IB4-negative small sensory neurons. Neuroscience 127:659–672PubMedGoogle Scholar
  186. Liu L, Hansen DR, Kim I, Gilbertson TA (2005) Expression and characterization of delayed rectifying K+ channels in anterior rat taste buds. Am J Physiol 289:C868–C880Google Scholar
  187. Liu L, Mansfield KJ, Kristiana I, Vaux KJ, Millard RJ, Burcher E (2007) The molecular basis of urgency: regional difference of vanilloid receptor expression in the human urinary bladder. Neurourol Urodyn 26:433–438PubMedGoogle Scholar
  188. LopezJimenez ND, Cavenagh MM, Sainz E, Cruz-Ithier MA, Battey JF, Sullivan SL (2006) Two members of the TRPP family of ion channels, Pkd1l3 and Pkd2l1, are co-expressed in a subset of taste receptor cells. J Neurochem 98:68–77PubMedGoogle Scholar
  189. López-López JR, Pérez-García MT (2007) An ASIC channel for acid chemotransduction. Circ Res 101:965–967PubMedGoogle Scholar
  190. Lu YX, Owyang C (1999) Duodenal acid-induced gastric relaxation is mediated by multiple pathways. Am J Physiol 276:G1501–G1506PubMedGoogle Scholar
  191. Ludwig MG, Vanek M, Guerini D, Gasser JA, Jones CE, Junker U, Hofstetter H, Wolf RM, Seuwen K (2003) Proton-sensing G-protein-coupled receptors. Nature 425:93–98PubMedGoogle Scholar
  192. Luger NM, Honore P, Sabino MA, Schwei MJ, Rogers SD, Mach DB, Clohisy DR, Mantyh PW (2001) Osteoprotegerin diminishes advanced bone cancer pain. Cancer Res 61:4038–4047PubMedGoogle Scholar
  193. Lyall V, Alam RI, Malik SA, Phan TH, Vinnikova AK, Heck GL, DeSimone JA (2004) Basolateral Na+-H+ exchanger-1 in rat taste receptor cells is involved in neural adaptation to acidic stimuli. J Physiol (Lond) 556:159–173Google Scholar
  194. Maingret F, Patel AJ, Lesage F, Lazdunski M, Honoré E (1999) Mechano- or acid stimulation, two interactive modes of activation of the TREK-1 potassium channel. J Biol Chem 274:26691–26696PubMedGoogle Scholar
  195. Maingret F, Lauritzen I, Patel AJ, Heurteaux C, Reyes R, Lesage F, Lazdunski M, Honoré E (2000) TREK-1 is a heat-activated background K+ channel. EMBO J 19:2483–2491PubMedGoogle Scholar
  196. Maingret F, Patel AJ, Lazdunski M, Honoré E (2001) The endocannabinoid anandamide is a direct and selective blocker of the background K+ channel TASK-1. EMBO J 20:47–54PubMedGoogle Scholar
  197. Mamet J, Baron A, Lazdunski M, Voilley N (2002) Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. J Neurosci 22:10662–10670PubMedGoogle Scholar
  198. Manela FD, Ren J, Gao J, McGuigan JE, Harty RF (1995) Calcitonin gene-related peptide modulates acid-mediated regulation of somatostatin and gastrin release from rat antrum. Gastroenterology 109:701–706PubMedGoogle Scholar
  199. Mao J, Li L, McManus M, Wu J, Cui N, Jiang C (2002) Molecular determinants for activation of G-protein-coupled inward rectifier K+ (GIRK) channels by extracellular acidosis. J Biol Chem 277:46166–46171PubMedGoogle Scholar
  200. Mathie A (2007) Neuronal two-pore-domain potassium channels and their regulation by G protein-coupled receptors. J Physiol (Lond) 578:377–385Google Scholar
  201. Matthews PJ, Aziz Q, Facer P, Davis JB, Thompson DG, Anand P (2004) Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus. Eur J Gastroenterol Hepatol 16:897–902PubMedGoogle Scholar
  202. Mazzuca M, Heurteaux C, Alloui A, Diochot S, Baron A, Voilley N, Blondeau N, Escoubas P, Gélot A, Cupo A, Zimmer A, Zimmer AM, Eschalier A, Lazdunski M (2007) A tarantula peptide against pain via ASIC1a channels and opioid mechanisms. Nat Neurosci 10:943–945PubMedGoogle Scholar
  203. McLatchie LM, Bevan S (2001) The effects of pH on the interaction between capsaicin and the vanilloid receptor in rat dorsal root ganglia neurons. Br J Pharmacol 132:899–908PubMedGoogle Scholar
  204. Meadows HJ, Randall AD (2001) Functional characterisation of human TASK-3, an acid-sensitive two-pore domain potassium channel. Neuropharmacology 40:551–559PubMedGoogle Scholar
  205. Medda BK, Sengupta JN, Lang IM, Shaker R (2005) Response properties of the brainstem neurons of the cat following intra-esophageal acid-pepsin infusion. Neuroscience 135:1285–1294PubMedGoogle Scholar
  206. Medhurst AD, Rennie G, Chapman CG, Meadows H, Duckworth MD, Kelsell RE, Gloger II, Pangalos MN (2001) Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery. Mol Brain Res 86:101–114PubMedGoogle Scholar
  207. Michael GJ, Priestley JV (1999) Differential expression of the mRNA for the vanilloid receptor subtype 1 in cells of the adult rat dorsal root and nodose ganglia and its downregulation by axotomy. J Neurosci 19:1844–1854PubMedGoogle Scholar
  208. Miller P, Peers C, Kemp PJ (2004) Polymodal regulation of hTREK1 by pH, arachidonic acid, and hypoxia: physiological impact in acidosis and alkalosis. Am J Physiol 286:C272–C282Google Scholar
  209. Miranda A, Nordstrom E, Mannem A, Smith C, Banerjee B, Sengupta JN (2007) The role of transient receptor potential vanilloid 1 in mechanical and chemical visceral hyperalgesia following experimental colitis. Neuroscience 148:1021–1032PubMedGoogle Scholar
  210. Mistrík P, Torre V (2004) Histidine 518 in the S6-CNBD linker controls pH dependence and gating of HCN channel from sea-urchin sperm. Pflugers Arch 448:76–84PubMedGoogle Scholar
  211. Mizuno A, Matsumoto N, Imai M, Suzuki M (2003) Impaired osmotic sensation in mice lacking TRPV4. Am J Physiol 285:C96–C101Google Scholar
  212. Mogil JS, Breese NM, Witty MF, Ritchie J, Rainville ML, Ase A, Abbadi N, Stucky CL, Seguela P (2005) Transgenic expression of a dominant-negative ASIC3 subunit leads to increased sensitivity to mechanical and inflammatory stimuli. J Neurosci 25:9893–9901PubMedGoogle Scholar
  213. Montrose MH, Akiba Y, Takeuchi K, Kaunitz JD (2006) Gastroduodenal mucosal defense. In: Johnson LR (ed) Physiology of the gastrointestinal tract, 4th edn. Academic, San Diego, pp 1259–1291Google Scholar
  214. Morenilla-Palao C, Planells-Cases R, García-Sanz N, Ferrer-Montiel A (2004) Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity. J Biol Chem 279:25665–25672PubMedGoogle Scholar
  215. Morton MJ, O'Connell AD, Sivaprasadarao A, Hunter M (2003) Determinants of pH sensing in the two-pore domain K+ channels TASK-1 and -2. Pflügers Arch 445:577–583PubMedGoogle Scholar
  216. Morton MJ, Abohamed A, Sivaprasadarao A, Hunter M (2005) pH sensing in the two-pore domain K+ channel, TASK2. Proc Natl Acad Sci USA 102:16102–16106PubMedGoogle Scholar
  217. Nagae M, Hiraga T, Wakabayashi H, Wang L, Iwata K, Yoneda T (2006) Osteoclasts play a part in pain due to the inflammation adjacent to bone. Bone 39:1107–1115PubMedGoogle Scholar
  218. Nagae M, Hiraga T, Yoneda T (2007) Acidic microenvironment created by osteoclasts causes bone pain associated with tumor colonization. J Bone Miner Metab 25:99–104PubMedGoogle Scholar
  219. Neelands TR, Jarvis MF, Han P, Faltynek CR, Surowy CS (2005) Acidification of rat TRPV1 alters the kinetics of capsaicin responses. Mol Pain 1:28PubMedGoogle Scholar
  220. Newell K, Franchi A, Pouysségur J, Tannock I (1993) Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity. Proc Natl Acad Sci USA 90:1127–1131PubMedGoogle Scholar
  221. Niemeyer MI, González-Nilo FD, Zúñiga L, González W, Cid LP, Sepúlveda FV (2007) Neutralization of a single arginine residue gates open a two-pore domain, alkali-activated K+ channel. Proc Natl Acad Sci USA 104:666–671PubMedGoogle Scholar
  222. Nomura H, Turco AE, Pei Y, Kalaydjieva L, Schiavello T, Weremowicz S, Ji W, Morton CC, Meisler M, Reeders ST, Zhou J (1998) Identification of PKDL, a novel polycystic kidney disease 2-like gene whose murine homologue is deleted in mice with kidney and retinal defects. J Biol Chem 273:25967–25973PubMedGoogle Scholar
  223. North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067PubMedGoogle Scholar
  224. Nugent SG, Kumar D, Rampton DS, Evans DF (2001) Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs. Gut 48:71–577Google Scholar
  225. Ohtori S, Inoue G, Koshi T, Ito T, Doya H, Saito T, Moriya H, Takahashi K (2006) Up-regulation of acid-sensing ion channel 3 in dorsal root ganglion neurons following application of nucleus pulposus on nerve root in rats. Spine 31:2048–2052PubMedGoogle Scholar
  226. Ohtori S, Inoue G, Koshi T, Ito T, Watanabe T, Yamashita M, Yamauchi K, Suzuki M, Doya H, Moriya H, Takahashi Y, Takahashi K (2007) Sensory innervation of lumbar vertebral bodies in rats. Spine 32:1498–1502PubMedGoogle Scholar
  227. Page AJ, Brierley SM, Martin CM, Price MP, Symonds E, Butler R, Wemmie JA, Blackshaw LA (2005) Different contributions of ASIC channels 1a, 2, and 3 in gastrointestinal mechanosensory function. Gut 54:1408–1415PubMedGoogle Scholar
  228. Page AJ, Brierley SM, Martin CM, Hughes PA, Blackshaw LA (2007) Acid sensing ion channels 2 and 3 are required for inhibition of visceral nociceptors by benzamil. Pain 133:150–160PubMedGoogle Scholar
  229. Patapoutian A, Peier AM, Story GM, Viswanath V (2003) ThermoTRP channels and beyond: mechanisms of temperature sensation. Nat Rev Neurosci 4:529–539PubMedGoogle Scholar
  230. Patel AJ, Honoré E (2001) Properties and modulation of mammalian 2P domain K+ channels. Trends Neurosci 24:339–346PubMedGoogle Scholar
  231. Patel AJ, Maingret F, Magnone V, Fosset M, Lazdunski M, Honoré E (2000) TWIK-2, an inactivating 2P domain K+ channel. J Biol Chem 275:28722–28730PubMedGoogle Scholar
  232. Patterson LM, Zheng H, Ward SM, Berthoud HR (2003) Vanilloid receptor (VR1) expression in vagal afferent neurons innervating the gastrointestinal tract. Cell Tissue Res 311:277–287PubMedGoogle Scholar
  233. Petersen M, LaMotte RH (1993) Effect of protons on the inward current evoked by capsaicin in isolated dorsal root ganglion cells. Pain 54:37–42PubMedGoogle Scholar
  234. Petheo GL, Molnár Z, Róka A, Makara JK, Spät A (2001) A pH-sensitive chloride current in the chemoreceptor cell of rat carotid body. J Physiol (Lond) 535:95–106Google Scholar
  235. Planells-Cases R, Garcìa-Sanz N, Morenilla-Palao C, Ferrer-Montiel A (2005) Functional aspects and mechanisms of TRPV1 involvement in neurogenic inflammation that leads to thermal hyperalgesia. Pflügers Arch 451:151–159PubMedGoogle Scholar
  236. Poirot O, Vukicevic M, Boesch A, Kellenberger S (2004) Selective regulation of acid-sensing ion channel 1 by serine proteases. J Biol Chem 279:38448–38457PubMedGoogle Scholar
  237. Poirot O, Berta T, Decosterd I, Kellenberger S (2006) Distinct ASIC currents are expressed in rat putative nociceptors and are modulated by nerve injury. J Physiol (Lond) 576:215–234Google Scholar
  238. Price MP, McIlwrath SL, Xie J, Cheng C, Qiao J, Tarr DE, Sluka KA, Brennan TJ, Lewin GR, Welsh MJ (2001) The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 32:1071–1083PubMedGoogle Scholar
  239. Putnam RW, Filosa JA, Ritucci NA (2004) Cellular mechanisms involved in CO2 and acid signaling in chemosensitive neurons. Am J Physiol 287:C1493–C1526Google Scholar
  240. Rajan S, Wischmeyer E, Xin Liu G, Preisig-Müller R, Daut J, Karschin A, Derst C (2000) TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histidine as pH sensor. J Biol Chem 275:16650–16657PubMedGoogle Scholar
  241. Rajan S, Plant LD, Rabin ML, Butler MH, Goldstein SA (2005) Sumoylation silences the plasma membrane leak K+ channel K2P1. Cell 121:37–47PubMedGoogle Scholar
  242. Rau KK, Cooper BY, Johnson RD (2006) Expression of TWIK-related acid sensitive K+ channels in capsaicin sensitive and insensitive cells of rat dorsal root ganglia. Neuroscience 141:955–963PubMedGoogle Scholar
  243. Reeh PW, Kress M (2001) Molecular physiology of proton transduction in nociceptors. Curr Opin Pharmacol 1:45–51PubMedGoogle Scholar
  244. Reyes R, Duprat F, Lesage F, Fink M, Salinas M, Farman N, Lazdunski M (1998) Cloning and expression of a novel pH-sensitive two pore domain K+ channel from human kidney. J Biol Chem 273:30863–30869PubMedGoogle Scholar
  245. Reyes R, Lauritzen I, Lesage F, Ettaiche M, Fosset M, Lazdunski M (2000) Immunolocalization of the arachidonic acid and mechanosensitive baseline TRAAK potassium channel in the nervous system. Neuroscience 95:893–901PubMedGoogle Scholar
  246. Ricciardolo FL, Gaston B, Hunt J (2004) Acid stress in the pathology of asthma. J Allergy Clin Immunol 113:610–619PubMedGoogle Scholar
  247. Richter TA, Dvoryanchikov GA, Chaudhari N, Roper SD (2004a) Acid-sensitive two-pore domain potassium (K2P) channels in mouse taste buds. J Neurophysiol 92:1928–1936PubMedGoogle Scholar
  248. Richter TA, Dvoryanchikov GA, Roper SD, Chaudhari N (2004b) Acid-sensing ion channel-2 is not necessary for sour taste in mice. J Neurosci 24:4088–4091PubMedGoogle Scholar
  249. Rigoni M, Trevisani M, Gazzieri D, Nadaletto R, Tognetto M, Creminon C, Davis JB, Campi B, Amadesi S, Geppetti P, Harrison S (2003) Neurogenic responses mediated by vanilloid receptor-1 (TRPV1) are blocked by the high affinity antagonist, iodo-resiniferatoxin. Br J Pharmacol 138:977–985PubMedGoogle Scholar
  250. Robinson DR, McNaughton PA, Evans ML, Hicks GA (2004) Characterization of the primary spinal afferent innervation of the mouse colon using retrograde labelling. Neurogastroenterol Motil 16:113–124PubMedGoogle Scholar
  251. 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 23:11315–11321PubMedGoogle Scholar
  252. Rong W, Hillsley K, Davis JB, Hicks G, Winchester WJ, Grundy D (2004) Jejunal afferent nerve sensitivity in wild-type and TRPV1 knockout mice. J Physiol (Lond) 560:867–881Google Scholar
  253. Rukwied R, Chizh BA, Lorenz U, Obreja O, Margarit S, Schley M, Schmelz M (2007) Potentiation of nociceptive responses to low pH injections in humans by prostaglandin E2. J Pain 8:443–451PubMedGoogle Scholar
  254. Ryu S, Liu B, Qin F (2003) Low pH potentiates both capsaicin binding and channel gating of VR1 receptors. J Gen Physiol 122:45–61PubMedGoogle Scholar
  255. Ryu S, Liu B, Yao J, Fu Q, Qin F (2007) Uncoupling proton activation of vanilloid receptor TRPV1. J Neurosci 27:12797–12807PubMedGoogle Scholar
  256. Sano Y, Inamura K, Miyake A, Mochizuki S, Kitada C, Yokoi H, Nozawa K, Okada H, Matsushime H, Furuichi K (2003) A novel two-pore domain K+ channel, TRESK, is localized in the spinal cord. J Biol Chem 278:27406–27412PubMedGoogle Scholar
  257. Schicho R, Schemann M, Pabst MA, Holzer P, Lippe IT (2003) Capsaicin-sensitive extrinsic afferents are involved in acid-induced activation of distinct myenteric neurons in the rat stomach. Neurogastroenterol Motil 15:33–44PubMedGoogle Scholar
  258. Schicho R, Florian W, Liebmann I, Holzer P, Lippe IT (2004) Increased expression of TRPV1 receptor in dorsal root ganglia by acid insult of the rat gastric mucosa. Eur J Neurosci 19:1811–1818PubMedGoogle Scholar
  259. Schmidt B, Hammer J, Holzer P, Hammer HF (2004) Chemical nociception in the jejunum induced by capsaicin. Gut 53:1109–1116PubMedGoogle Scholar
  260. Schuligoi R, Jocic M, Heinemann A, Schöninkle E, Pabst MA, Holzer P (1998) Gastric acid-evoked c-fos messenger RNA expression in rat brainstem is signaled by capsaicin-resistant vagal afferents. Gastroenterology 115:649–660PubMedGoogle Scholar
  261. Seabrook GR, Sutton KG, Jarolimek W, Hollingworth GJ, Teague S, Webb J, Clark N, Boyce S, Kerby J, Ali Z, Chou M, Middleton R, Kaczorowski G, Jones AB (2002) Functional properties of the high-affinity TRPV1 (VR1) vanilloid receptor antagonist (4-hydroxy-5-iodo-3-methoxyphenylacetate ester) iodo-resiniferatoxin. J Pharmacol Exp Ther 303:1052–1060PubMedGoogle Scholar
  262. Semtner M, Schaefer M, Pinkenburg O, Plant TD (2007) Potentiation of TRPC5 by protons. J Biol Chem 282:33868–33878PubMedGoogle Scholar
  263. Shimada S, Ueda T, Ishida Y, Yamamoto T, Ugawa S (2006) Acid-sensing ion channels in taste buds. Arch Histol Cytol 69:227–231PubMedGoogle Scholar
  264. Shimokawa N, Dikic I, Sugama S, Koibuchi N (2005) Molecular responses to acidosis of central chemosensitive neurons in brain. Cell Signal 17:799–808PubMedGoogle Scholar
  265. Shulkes A, Baldwin GS, Giraud AS (2006) Regulation of gastric acid secretion. In: Johnson LR (ed) Physiology of the gastrointestinal tract, 4th edn. Academic, San Diego, pp 1223–1258Google Scholar
  266. Sluka KA, Price MP, Breese NA, Stucky CL, Wemmie JA, Welsh MJ (2003) Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1. Pain 106:229–239PubMedGoogle Scholar
  267. Sluka KA, Radhakrishnan R, Benson CJ, Eshcol JO, Price MP, Babinski K, Audette KM, Yeomans DC, Wilson SP (2007) ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation. Pain 129:102–112PubMedGoogle Scholar
  268. Smith ES, Cadiou H, McNaughton PA (2007) Arachidonic acid potentiates acid-sensing ion channels in rat sensory neurons by a direct action. Neuroscience 145:686–698PubMedGoogle Scholar
  269. Somodi S, Varga Z, Hajdu P, Starkus JG, Levy DI, Gáspár R, Panyi G (2004) pH-dependent modulation of Kv1.3 inactivation: role of His399. Am J Physiol 287:C1067–C1076Google Scholar
  270. Steen KH, Reeh PW (1993) Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in human skin. Neurosci Lett 154:113–116PubMedGoogle Scholar
  271. Steen KH, Reeh PW, Anton F, Handwerker HO (1992) Protons selectively induce lasting excitation and sensitization to mechanical stimulation of nociceptors in rat skin, in vitro. J Neurosci 12:86–95PubMedGoogle Scholar
  272. Steen KH, Reeh PW, Kreysel HW (1995) Topical acetylsalicylic, salicylic acid and indomethacin suppress pain from experimental tissue acidosis in human skin. Pain 62:339–347PubMedGoogle Scholar
  273. Stevens DR, Seifert R, Bufe B, Müller F, Kremmer E, Gauss R, Meyerhof W, Kaupp UB, Lindemann B (2001) Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli. Nature 413:631–635PubMedGoogle Scholar
  274. Stoop R, Surprenant A, North RA (1997) Different sensitivities to pH of ATP-induced currents at four cloned P2X receptors. J Neurophysiol 78:1837–1840PubMedGoogle Scholar
  275. Strecker T, Messlinger K, Weyand M, Reeh PW (2005) Role of different proton-sensitive channels in releasing calcitonin gene-related peptide from isolated hearts of mutant mice. Cardiovasc Res 65:405–410PubMedGoogle Scholar
  276. Sugiura T, Dang K, Lamb K, Bielefeldt K, Gebhart GF (2005) Acid-sensing properties in rat gastric sensory neurons from normal and ulcerated stomach. J Neurosci 25:2617–2627PubMedGoogle Scholar
  277. Sugiura T, Bielefeldt K, Gebhart GF (2007) Mouse colon sensory neurons detect extracellular acidosis via TRPV1. Am J Physiol 292:C1768–C1774Google Scholar
  278. Surprenant A, Schneider DA, Wilson HL, Galligan JJ, North RA (2000) Functional properties of heteromeric P2X1/5 receptors expressed in HEK cells and excitatory junction potentials in guinea-pig submucosal arterioles. J Auton Nerv Syst 81:249–263PubMedGoogle Scholar
  279. Sutherland SP, Benson CJ, Adelman JP, McCleskey EW (2001) Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proc Natl Acad Aci USA 98:711–716Google Scholar
  280. Suzuki M, Mizuno A, Kodaira K, Imai M (2003a) Impaired pressure sensation in mice lacking TRPV4. J Biol Chem 278:22664–22668PubMedGoogle Scholar
  281. Suzuki M, Watanabe Y, Oyama Y, Mizuno A, Kusano E, Hirao A, Ookawara S (2003b) Localization of mechanosensitive channel TRPV4 in mouse skin. Neurosci Lett 353:189–192PubMedGoogle Scholar
  282. Szallasi A, Blumberg PM (1999) Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 51:159–212PubMedGoogle Scholar
  283. Szallasi A, Cortright DN, Blum CA, Eid SR (2007) The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 6:357–372PubMedGoogle Scholar
  284. Szelényi Z, Hummel Z, Szolcsányi J, Davis JB (2004) Daily body temperature rhythm and heat tolerance in TRPV1 knockout and capsaicin pretreated mice. Eur J Neurosci 19:1421–1424PubMedGoogle Scholar
  285. Talley EM, Solorzano G, Lei Q, Kim D, Bayliss DA (2001) CNS distribution of members of the two-pore-domain (KCNK) potassium channel family. J Neurosci 21:7491–7505PubMedGoogle Scholar
  286. Tan ZY, Lu Y, Whiteis CA, Benson CJ, Chapleau MW, Abboud FM (2007) Acid-sensing ion channels contribute to transduction of extracellular acidosis in rat carotid body glomus cells. Circ Res 101:1009–1019PubMedGoogle Scholar
  287. Tang L, Chen Y, Chen Z, Blumberg PM, Kozikowski AP, Wang ZJ (2007) Antinociceptive pharmacology of N-(4-chlorobenzyl)-N′-(4-hydroxy-3-iodo-5-methoxybenzyl) thiourea, a high-affinity competitive antagonist of the transient receptor potential vanilloid 1 receptor. J Pharmacol Exp Ther 321:791–798PubMedGoogle Scholar
  288. Tashima K, Nakashima M, Kagawa S, Kato S, Takeuchi K (2002) Gastric hyperemic response induced by acid back-diffusion in rat stomachs following barrier disruption – relation to vanilloid type-1 receptors. Med Sci Monit 8:BR157–BR163PubMedGoogle Scholar
  289. Tominaga M, Caterina M, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21:531–543PubMedGoogle Scholar
  290. Tomura H, Mogi C, Sato K, Okajima F (2005) Proton-sensing and lysolipid-sensitive G-protein-coupled receptors: a novel type of multi-functional receptors. Cell Signal 17:1466–1476PubMedGoogle Scholar
  291. Trevisani M, Milan A, Gatti R, Zanasi A, Harrison S, Fontana G, Morice AH, Geppetti P (2004) Antitussive activity of iodo-resiniferatoxin in guinea pigs. Thorax 59:769–772PubMedGoogle Scholar
  292. Uchiyama Y, Cheng CC, Danielson KG, Mochida J, Albert TJ, Shapiro IM, Risbud MV (2007) Expression of acid-sensing ion channel 3 (ASIC3) in nucleus pulposus cells of the intervertebral disc is regulated by p75NTR and ERK signaling. J Bone Miner Res 22:1996–2006PubMedGoogle Scholar
  293. Ugawa S, Ueda T, Ishida Y, Nishigaki M, Shibata Y, Shimada S (2002) Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. J Clin Invest 110:1185–1190PubMedGoogle Scholar
  294. Ugawa S, Yamamoto T, Ueda T, Ishida Y, Inagaki A, Nishigaki M, Shimada S (2003) Amiloride-insensitive currents of the acid-sensing ion channel-2a (ASIC2a)/ASIC2b heteromeric sour-taste receptor channel. J Neurosci 23:3616–3622PubMedGoogle Scholar
  295. Ugawa S, Ueda T, Yamamura H, Shimada S (2005) In situ hybridization evidence for the coexistence of ASIC and TRPV1 within rat single sensory neurons. Mol Brain Res 136:125–133PubMedGoogle Scholar
  296. Urban L, Campbell EA, Panesar M, Patel S, Chaudhry N, Kane S, Buchheit K, Sandells B, James IF (2000) In vivo pharmacology of SDZ 249-665, a novel, non-pungent capsaicin analogue. Pain 89:65–74PubMedGoogle Scholar
  297. Van Buren JJ, Bhat S, Rotello R, Pauza ME, Premkumar LS (2005) Sensitization and translocation of TRPV1 by insulin and IGF-I. Mol Pain 1:17PubMedGoogle Scholar
  298. Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465PubMedGoogle Scholar
  299. Vellani V, Mapplebeck S, Moriondo A, Davis JB, McNaughton PA (2001) Protein kinase C activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide. J Physiol 534:813–825PubMedGoogle Scholar
  300. Voilley N, de Weille J, Mamet J, Lazdunski M (2001) Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors. J Neurosci 21:8026–8033PubMedGoogle Scholar
  301. Vulcu SD, Liewald JF, Gillen C, Rupp J, Nawrath H (2004) Proton conductance of human transient receptor potential-vanilloid type-1 expressed in oocytes of Xenopus laevis and in Chinese hamster ovary cells. Neuroscience 125:861–866PubMedGoogle Scholar
  302. Wachter CH, Heinemann A, Donnerer J, Pabst MA, Holzer P (1998) Mediation by 5-hydroxytryptamine of the femoral vasoconstriction induced by acid challenge of the rat gastric mucosa. J Physiol (Lond) 509:541–550Google Scholar
  303. Waldmann R (2001) Proton-gated cation channels – neuronal acid sensors in the central and peripheral nervous system. Adv Exp Med Biol 502:293–304PubMedGoogle Scholar
  304. Waldmann R, Lazdunski M (1998) H+-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels. Curr Opin Neurobiol 8:418–424PubMedGoogle Scholar
  305. Waldmann R, Champigny G, Lingueglia E, De Weille JR, Heurteaux C, Lazdunski M (1999) H+-gated cation channels. Ann N Y Acad Sci 868:67–76PubMedGoogle Scholar
  306. Wang L, Wang DH (2005) TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice. Circulation 112:3617–3623PubMedGoogle Scholar
  307. Wang X, Wu J, Li L, Chen F, Wang R, Jiang C (2003) Hypercapnic acidosis activates KATP channels in vascular smooth muscles. Circ Res 92:1225–1232PubMedGoogle Scholar
  308. Welch JM, Simon SA, Reinhart PH (2000) The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat. Proc Natl Acad Sci USA 97:13889–13894PubMedGoogle Scholar
  309. Welsh MJ, Price MP, Xie J (2002) Biochemical basis of touch perception: mechanosensory function of degenerin/epithelial Na+ channels. J Biol Chem 277:2369–2372PubMedGoogle Scholar
  310. Wemmie JA, Price MP, Welsh MJ (2006) Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci 29:578–586PubMedGoogle Scholar
  311. Wildman SS, Brown SG, Rahman M, Noel CA, Churchill L, Burnstock G, Unwin RJ, King BF (2002) Sensitization by extracellular Ca2+ of rat P2X5 receptor and its pharmacological properties compared with rat P2X1. Mol Pharmacol 62:957–966PubMedGoogle Scholar
  312. Woodbury CJ, Zwick M, Wang S, Lawson JJ, Caterina MJ, Koltzenburg M, Albers KM, Koerber HR, Davis BM (2004) Nociceptors lacking TRPV1 and TRPV2 have normal heat responses. J Neurosci 24:6410–6415PubMedGoogle Scholar
  313. Wultsch T, Painsipp E, Shahbazian A, Mitrovic M, Edelsbrunner M, Waldmann R, Lazdunski M, Holzer P (2008) Deletion of the acid-sensing ion channel ASIC3 prevents gastritis-induced acid hyperresponsiveness of the stomach-brainstem axis. Pain 134:245–253PubMedGoogle Scholar
  314. Wynn G, Ma B, Ruan HZ, Burnstock G (2004) Purinergic component of mechanosensory transduction is increased in a rat model of colitis. Am J Physiol 287:G647–G657Google Scholar
  315. Xie J, Price MP, Berger AL, Welsh MJ (2002) DRASIC contributes to pH-gated currents in large dorsal root ganglion sensory neurons by forming heteromultimeric channels. J Neurophysiol 87:2835–2843PubMedGoogle Scholar
  316. Xiong ZG, Chu XP, Simon RP (2006) Ca2+-permeable acid-sensing ion channels and ischemic brain injury. J Membr Biol 209:59–68PubMedGoogle Scholar
  317. Xu GY, Huang LY (2002) Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. J Neurosci 22:93–102PubMedGoogle Scholar
  318. Xu GY, Winston JH, Shenoy M, Yin H, Pendyala S, Pasricha PJ (2007) Transient receptor potential vanilloid 1 mediates hyperalgesia and is up-regulated in rats with chronic pancreatitis. Gastroenterology 133:1282–1292PubMedGoogle Scholar
  319. Xu H, Cui N, Yang Z, Wu J, Giwa LR, Abdulkadir L, Sharma P, Jiang C (2001) Direct activation of cloned KATP channels by intracellular acidosis. J Biol Chem 276:12898–12902PubMedGoogle Scholar
  320. Yagi J, Wenk HN, Naves LA, McCleskey EW (2006) Sustained currents through ASIC3 ion channels at the modest pH changes that occur during myocardial ischemia. Circ Res 99:501–509PubMedGoogle Scholar
  321. Yang HYT, Tao T, Iadarola MJ (2008) Modulatory role of neuropeptide FF system in nociception and opiate analgesia. Neuropeptides 42:1–18PubMedGoogle Scholar
  322. Yiangou Y, Facer P, Baecker PA, Ford AP, Knowles CH, Chan CL, Williams NS, Anand P (2001a) ATP-gated ion channel P2X3 is increased in human inflammatory bowel disease. Neurogastroenterol Motil 13:365–369PubMedGoogle Scholar
  323. Yiangou Y, Facer P, Dyer NH, Chan CL, Knowles C, Williams NS, Anand P (2001b) Vanilloid receptor 1 immunoreactivity in inflamed human bowel. Lancet 357:1338–1339PubMedGoogle Scholar
  324. Yiangou Y, Facer P, Smith JA, Sangameswaran L, Eglen R, Birch R, Knowles C, Williams N, Anand P (2001c) Increased acid-sensing ion channel ASIC-3 in inflamed human intestine. Eur J Gastroenterol Hepatol 13:891–896PubMedGoogle Scholar
  325. Yuill K, Ashmole I, Stanfield PR (2004) The selectivity filter of the tandem pore potassium channel TASK-1 and its pH-sensitivity and ionic selectivity. Pflugers Arch 448:63–69PubMedGoogle Scholar
  326. Yuill KH, Stansfeld PJ, Ashmole I, Sutcliffe MJ, Stanfield PR (2007) The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1: contributions of the pore domains. Pflugers Arch 455:333–348PubMedGoogle Scholar
  327. Zeilhofer HU, Swandulla D, Reeh PW, Kress M (1996) Ca2+ permeability of the sustained proton-induced cation current in adult rat dorsal root ganglion neurons. J Neurophysiol 76:2834–2840PubMedGoogle Scholar
  328. Zeilhofer HU, Kress M, Swandulla D (1997) Fractional Ca2+ currents through capsaicin- and proton-activated ion channels in rat dorsal root ganglion neurones. J Physiol (Lond) 503:67–78Google Scholar
  329. Zhang M, Nurse CA (2004) CO2/pH chemosensory signaling in co-cultures of rat carotid body receptors and petrosal neurons: role of ATP and Ach. J Neurophysiol 92:3433–3445PubMedGoogle Scholar
  330. Zhang X, Huang J, McNaughton PA (2005) NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J 24:4211–4223PubMedGoogle Scholar
  331. Zhong B, Wang DH (2007) TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice. Am J Physiol 293:H1791–H1798Google Scholar
  332. Zhong Y, Dunn PM, Bardini M, Ford APDW, Cockayne DA, Burnstock G (2001) Changes in P2X receptor responses of sensory neurons from P2X3-deficient mice. Eur J Neurosci 14:1784–1792PubMedGoogle Scholar
  333. Zong X, Stieber J, Ludwig A, Hofmann F, Biel M (2001) A single histidine residue determines the pH sensitivity of the pacemaker channel HCN2. J Biol Chem 276:6313–6319PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical PharmacologyMedical University of GrazGrazAustria

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