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The transient receptor potential channel TRPA1: from gene to pathophysiology

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Abstract

The Transient Receptor Potential Ankyrin 1 channel (TRPA1), is a member of the large TRP family of ion channels, and functions as a Ca2+ permeable non-selective cation channel in many different cell processes, ranging from sensory to homeostatic tasks. TRPA1 is highly conserved across the animal kingdom. The only mammalian TRPA subfamily member, TRPA1, is widely expressed in neuronal (e.g. sensory dorsal root and trigeminal ganglia neurons)- and in non-neuronal cells (e.g. epithelial cells, hair cells). It exhibits 14–19 amino-(N-)terminal ankyrin repeats, an unusual structural feature. The TRPA1 channel is activated by noxious cold (<17 °C) as well as by a plethora of chemical compounds that includes not only electrophilic compounds and oxidants that can modify, in an alkylative or oxidative fashion, nucleophilic cysteine residues in the channel’s N-terminus, but also compounds that do not covalently bind to the channel proteins (e.g. menthol, nifedipin). Based on localization and functional properties, TRPA1 is considered a key player in acute and chronic (neuropathic) pain and inflammation. Moreover, its role in the (patho)physiology of nearly all organ systems is anticipated, and will be discussed along with the potential of TRPA1 as a drug target for the management of various pathological conditions.

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References

  1. Alenmyr L, Herrmann A, Hogestatt ED, Greiff L, Zygmunt PM (2011) TRPV1 and TRPA1 stimulation induces MUC5B secretion in the human nasal airway in vivo. Clin Physiol Funct Imaging 31:435–444

    PubMed  CAS  Google Scholar 

  2. Andersson DA, Gentry C, Alenmyr L, Killander D, Lewis SE, Andersson A, Bucher B, Galzi JL, Sterner O, Bevan S, Hogestatt ED, Zygmunt PM (2011) TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Delta(9)-tetrahydrocannabiorcol. Nat Commun 2:551

    PubMed  Google Scholar 

  3. Andersson DA, Gentry C, Moss S, Bevan S (2008) Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci 28:2485–2494

    PubMed  CAS  Google Scholar 

  4. Andersson DA, Gentry C, Moss S, Bevan S (2009) Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn2+. Proc Natl Acad Sci (USA) 106:8374–8379

    CAS  Google Scholar 

  5. Andersson KE, Gratzke C, Hedlund P (2010) The role of the transient receptor potential (TRP) superfamily of cation-selective channels in the management of the overactive bladder. BJU Int 106:1114–1127

    PubMed  CAS  Google Scholar 

  6. Andrade EL, Ferreira J, Andre E, Calixto JB (2006) Contractile mechanisms coupled to TRPA1 receptor activation in rat urinary bladder. Biochem Pharmacol 72:104–114

    PubMed  CAS  Google Scholar 

  7. Andrade EL, Forner S, Bento AF, Leite DF, Dias MA, Leal PC, Koepp J, Calixto JB (2011) Trpa1 Receptor Modulation Attenuates Bladder Overactivity Induced by Spinal Cord Injury. Am J Physiol Ren Physiol 300:F1223–F1234

    CAS  Google Scholar 

  8. Andrade EL, Meotti FC, Calixto JB (2012) TRPA1 antagonists as potential analgesic drugs. Pharmacol Ther 133:189–204

    PubMed  CAS  Google Scholar 

  9. Andre E, Gatti R, Trevisani M, Preti D, Baraldi PG, Patacchini R, Geppetti P (2009) Transient receptor potential ankyrin receptor 1 is a novel target for pro-tussive agents. Br J Pharmacol 158:1621–1628

    PubMed  CAS  Google Scholar 

  10. Anke H, Sterner O (1991) Comparison of the antimicrobial and cytotoxic activities of twenty unsaturated sesquiterpene dialdehydes from plants and mushrooms. Planta Medica 57:344–346

    PubMed  CAS  Google Scholar 

  11. Artim DE, Bazely F, Daugherty SL, Sculptoreanu A, Koronowski KB, Schopfer FJ, Woodcock SR, Freeman BA, de Groat WC (2011) Nitro-oleic acid targets transient receptor potential (TRP) channels in capsaicin sensitive afferent nerves of rat urinary bladder. Exp Neurol 232:90–99

    PubMed  CAS  Google Scholar 

  12. Atoyan R, Shander D, Botchkareva NV (2009) Non-Neuronal Expression of Transient Receptor Potential Type A1 (TRPA1) in Human Skin. J Invest Dermatol 129:2312–2315

    PubMed  CAS  Google Scholar 

  13. Aubdool AA, Brain SD (2011) Neurovascular aspects of skin neurogenic inflammation. J Investig Dermatol Symp Proc 15:33–39

    PubMed  CAS  Google Scholar 

  14. Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41:849–857

    PubMed  CAS  Google Scholar 

  15. Bang S, Hwang SW (2009) Polymodal Ligand Sensitivity of TRPA1 and Its Modes of Interactions. J Gen Physiol 133:257–262

    PubMed  CAS  Google Scholar 

  16. Bang S, Kim KY, Yoo S, Kim YG, Hwang SW (2007) Transient receptor potential A1 mediates acetaldehyde-evoked pain sensation. Eur J Neurosci 26:2516–2523

    PubMed  Google Scholar 

  17. Bang S, Yoo S, Yang TJ, Cho H, Kim YG, Hwang SW (2010) Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception. Br J Pharmacol 161:707–720

    PubMed  CAS  Google Scholar 

  18. Banke TG (2011) The dilated TRPA1 channel pore state is blocked by amiloride and analogues. Brain Res 1381:21–30

    PubMed  CAS  Google Scholar 

  19. Banke T, Chaplan S, Wickenden AD (2010) Dynamic changes in the TRPA1 selectivity filter lead to progressive but reversible pore dilation. Am J Physiol Cell Physiol Cell Physiology 298:C1438–C1444

    Google Scholar 

  20. Baraldi PG, Preti D, Materazzi S, Geppetti P (2010) Transient Receptor Potential Ankyrin 1 (TRPA1) Channel as Emerging Target for Novel Analgesics and Anti-Inflammatory Agents. J Med Chem 53:5085–5107

    PubMed  CAS  Google Scholar 

  21. Baraldi PG, Romagnoli R, Saponaro G, Aghazadeh Tabrizi M, Baraldi S, Pedretti P, Fusi C, Nassini R, Materazzi S, Geppetti P, Preti D (2012) 7-Substituted-pyrrolo[3,2-d]pyrimidine-2,4-dione derivatives as antagonists of the transient receptor potential ankyrin 1 (TRPA1) channel: A promising approach for treating pain and inflammation. Bioorg Med Chem 20:1690–1698

    PubMed  CAS  Google Scholar 

  22. Bassoli A, Borgonovo G, Caimi S, Scaglioni L, Morini G, Moriello AS, Marzo VD, Petrocellis LD (2009) Taste-guided identification of high potency TRPA1 agonists from Perilla frutescens. Bioorg Med Chem 17:1636–1639

    PubMed  CAS  Google Scholar 

  23. Bautista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EN, Basbaum AI, Julius D (2006) TRPA1 Mediates the Inflammatory Actions of Environmental Irritants and Proalgesic Agents. Cell 124:1269–1282

    PubMed  CAS  Google Scholar 

  24. Bautista DM, Movahed P, Hinman A, Axelsson HE, Sterner O, Hogestatt ED, Julius D, Jordt SE, Zygmunt PM (2005) Pungent products from garlic activate the sensory ion channel TRPA1. Proc Natl Acad Sci U S A 102:12248–12252

    PubMed  CAS  Google Scholar 

  25. Bautista DM, Sigal YM, MilsteinA D, Garrison JL, Zorn JA, Tsuruda PR, Nicoll RA, Julius D (2008) Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nat Neurosci 11:772–779

    PubMed  CAS  Google Scholar 

  26. Belvisi MG, Dubuis E, Birrell MA (2011) Transient receptor potential A1 channels: insights into cough and airway inflammatory disease. Chest 140:1040–1047

    PubMed  CAS  Google Scholar 

  27. Benedikt J, Samad A, Ettrich R, Teisinger J, Vlachova V (2009) Essential role for the putative S6 inner pore region in the activation gating of the human TRPA1 channel. Biochim Biophys Acta 1793:1279–1288

    PubMed  CAS  Google Scholar 

  28. Bessac BF, Jordt S-E (2008) Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control. Physiology (Bethesda) 23:360–370

    CAS  Google Scholar 

  29. Bessac BF, Sivula M, von Hehn CA, Caceres AI, Escalera J, Jordt SE (2009) Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases. FASEB J 23:1102–1114

    PubMed  CAS  Google Scholar 

  30. Bessac BF, Sivula M, von Hehn CA, Escalera J, Cohn L, Jordt SE (2008) TRPA1 is a major oxidant sensor in murine airway sensory neurons. J Clin Investig 118:1899–1910

    PubMed  CAS  Google Scholar 

  31. Bianchi BR, Zhang XF, Reilly RM, Kym PR, Yao BB, Chen J (2012) Species comparison and pharmacological characterization of human, monkey, rat and mouse TRPA1 channels. J Pharmacol Exp Ther 341:360–368

    PubMed  CAS  Google Scholar 

  32. Binder A, May D, Baron R, Maier C, Tolle TR, Treede RD, Berthele A, Faltraco F, Flor H, Gierthmuhlen J, Haenisch S, Huge V, Magerl W, Maihofner C, Richter H, Rolke R, Scherens A, Uceyler N, Ufer M, Wasner G, Zhu J, Cascorbi I (2011) Transient receptor potential channel polymorphisms are associated with the somatosensory function in neuropathic pain patients. PLoS One 6:e17387

    PubMed  CAS  Google Scholar 

  33. Bobkov YV, Corey EA, Ache BW (2011) The pore properties of human nociceptor channel TRPA1 evaluated in single channel recordings. Biochim Biophys Acta 1808:1120–1128

    PubMed  CAS  Google Scholar 

  34. Brenneis C, Sisignano M, Coste O, Altenrath K, Fischer MJ, Angioni C, Fleming I, Brandes RP, Reeh PW, Woolf CJ, Geisslinger G, Scholich K (2011) Soluble epoxide hydrolase limits mechanical hyperalgesia during inflammation. Mol Pain 7:78

    PubMed  CAS  Google Scholar 

  35. Brierley SM, Castro J, Harrington AM, Hughes PA, Page AJ, Rychkov GY, Blackshaw LA (2011) TRPA1 contributes to specific mechanically activated currents and sensory neuron mechanical hypersensitivity. J Physiol 589:3575–3593

    PubMed  CAS  Google Scholar 

  36. Brierley SM, Hughes PA, Page AJ, Kwan KY, Martin CM, O’Donnell TA, Cooper NJ, Harrington AM, Adam B, Liebregts T, Holtmann G, Corey DP, Rychkov GY, Blackshaw LA (2009) The ion channel TRPA1 is required for normal mechanosensation and is modulated by algesic stimuli. Gastroenterology 137:2084–2095

    PubMed  CAS  Google Scholar 

  37. Brockhoff A, Behrens M, Massarotti A, Appendino G, Meyerhof W (2007) Broad tuning of the human bitter taste receptor hTAS2R46 to various sesquiterpene lactones, clerodane and labdane diterpenoids, strychnine, and denatonium. J Agric Food Chem 55:6236–6243

    PubMed  CAS  Google Scholar 

  38. Brooks SM (2010) Occupational, environmental, and irritant-induced cough. Otolaryngol Clin North Am 43:85–96

    PubMed  Google Scholar 

  39. Brooks SM, Bernstein IL (2011) Irritant-induced airway disorders. Immunol Allergy Clin North Am 31:747–768

    PubMed  Google Scholar 

  40. Brownlee M (2011) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    Google Scholar 

  41. Brozmanova M, Mazurova L, Ru F, Tatar M, Kollarik M (2012) Comparison of TRPA1-versus TRPV1- mediated Cough in Guinea Pigs. Eur J Pharmacol 689:211–218

    PubMed  CAS  Google Scholar 

  42. Brozmanova M, Ru F, Surdenikova L, Mazurova L, Taylor-Clark T, Kollarik M (2011) Preferential activation of the vagal nodose nociceptive subtype by TRPA1 agonists in the guinea pig esophagus. Neurogastroenterol Motil 23:e437–e445

    PubMed  CAS  Google Scholar 

  43. Byers MR, Westenbroek RE (2011) Odontoblasts in developing, mature and ageing rat teeth have multiple phenotypes that variably express all nine voltage-gated sodium channels. Arch Oral Biol 56:1199–1220

    PubMed  CAS  Google Scholar 

  44. Caceresa AI, Brackmann M, Elia MD, Bessac BF, del Caminob D, D’Amours M, Witek JS, Fanger CM, Chong JA, Hayward NJ, Homer RJ, Cohn L, Huang X, Moran MM, Jordt S-E (2009) A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc Natl Acad Sci (USA) 106:9099–9104

    Google Scholar 

  45. Cao DS, Zhong L, Hsieh TH, Abooj M, Bishnoi M, Hughes L, Premkumar LS (2012) Expression of Transient Receptor Potential Ankyrin 1 (TRPA1) and Its Role in Insulin Release from Rat Pancreatic Beta Cells. PLoS One 7:e38005

    PubMed  CAS  Google Scholar 

  46. Caspani O, Heppenstall PA (2009) TRPA1 and Cold Transduction: An Unresolved Issue? J Gen Physiol 133:245–249

    PubMed  CAS  Google Scholar 

  47. Caterina MJ (2007) Chemical biology: Sticky spices. Nature 445:491–492

    PubMed  CAS  Google Scholar 

  48. Cattaruzza F, Spreadbury I, Miranda-Morales M, Grady EF, Vanner SJ, Bunnett NW (2010) Transient Receptor Potential Ankyrin-1 has a Major Role in Mediating Visceral Pain in Mice. Am J Physiol Gastrointest Liver Physiol 298:G81–G91

    PubMed  CAS  Google Scholar 

  49. Cavanaugh EJ, Simkin D, Kim D (2008) Activation of TRPA1 by Mustard oil, Tetrahydrocannabinol and Ca2+ Reveals Different Functional States of TRPA1. Neuroscience 154:1467–1476

    PubMed  CAS  Google Scholar 

  50. Chatzigeorgiou M, Yoo S, Watson JD, Lee W-H, Spencer WC, Kindt KS, Hwang SW, Miller DM, Treinin M, Driscoll M, Schafer WR (2010) Specific roles for DEG/ENaC and TRP channels in touch and thermosensation in C. elegans nociceptors. Nat Neurosci 13:861–868

    PubMed  CAS  Google Scholar 

  51. Chen J, Joshi SK, Didomenico S, Perner RJ, Mikusa JP, Gauvin DM, Segreti JA, Han P, Zhang XF, Niforatos W, Bianchi BR, Baker SJ, Zhong C, Simler GH, McDonald HA, Schmidt RG, McGaraughty SP, Chu KL, Faltynek CR, Kort ME, Reilly RM, Kym PR (2011) Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation. Pain 152:1165–1172

    PubMed  CAS  Google Scholar 

  52. Chen J, Kim D, Bianchi BR, Cavanaugh EJ, Faltynek CR, Kym PR, Reilly RM (2009) Pore dilation occurs in TRPA1 but not in TRPM8 channels. Mol Pain 5:3

    PubMed  Google Scholar 

  53. Chen J, Zhang XF, Kort ME, Huth JR, Sun C, Miesbauer LJ, Cassar SC, Neelands T, Scott VE, Moreland RB, Reilly RM, Hajduk PJ, Kym PR, Hutchins CW, Faltynek CR (2008) Molecular determinants of species-specific activation or blockade of TRPA1 channels. J Neurosci 28:5063–5071

    PubMed  CAS  Google Scholar 

  54. Cho JH, Jeong MY, Choi IS, Lee HJ, Jang IS (2012) TRPA1-like channels enhance glycinergic transmission in medullary dorsal horn neurons. J Neurochem 122:691–701

    PubMed  CAS  Google Scholar 

  55. Choi MJ, Jin Z, Park YS, Rhee YK, Jin YH (2011) Transient receptor potential (TRP) A1 activated currents in TRPV1 and cholecystokinin-sensitive cranial visceral afferent neurons. Brain Res 1383:36–42

    PubMed  CAS  Google Scholar 

  56. Christianson JA, Bielefeldt K, Malin SA, Davis BM (2010) Neonatal colon insult alters growth factor expression and TRPA1 responses in adult mice. Pain 151:540–549

    PubMed  CAS  Google Scholar 

  57. Ciobanu C, Reid G, Babes A (2009) Acute and chronic effects of neurotrophic factors BDNF and GDNF on responses mediated by thermo-sensitive TRP channels in cultured rat dorsal root ganglion neurons. Brain Res 1284:54–67

    PubMed  CAS  Google Scholar 

  58. Clapham DE, Nilius B, Owsianik G (2009) Transient receptor potential channels. Last modified on 2009-10-14. (IUPHAR-DB). http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=78

  59. Cordero-Morales JF, Gracheva EO, Julius D (2011) Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli. Proc Natl Acad Sci U S A 108:E1184–E1191

    PubMed  CAS  Google Scholar 

  60. Corey DP, Garcia-Anoveros J, Holt JR, Kwan KY, Lin SY, Vollrath MA, Amalfitano A, Cheung EL, Derfler BH, Duggan A, Geleoc GS, Gray PA, Hoffman MP, Rehm HL, Tamasauskas D, Zhang DS (2004) TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature 432:723–730

    PubMed  CAS  Google Scholar 

  61. Cruz-Orengo L, Dhaka A, Heuermann RJ, Young TJ, Montana MC, Cavanaugh EJ, Kim D, Story GM (2008) Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1. Mol Pain 4:30

    PubMed  Google Scholar 

  62. Cvetkov TL, Huynh KW, Cohen MR, Moiseenkova-Bell VY (2011) Molecular architecture and subunit organization of TRPA1 channel revealed by electron microscopy. J Biol Chem 286:38168–38176

    PubMed  CAS  Google Scholar 

  63. Dai Y, Wang S, Tominaga M, Yamamoto S, Fukuoka T, Higashi T, Kobayashi K, Obata K, Yamanaka H, Noguchi K (2007) Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J Clin Investig 117:1978–1987

    Google Scholar 

  64. De Petrocellis L, Ligresti A, Moriello AS, Allara M, Bisogno T, Petrosino S, Stott CG, Di Marzo V (2010) Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 163:1479–1494

    Google Scholar 

  65. De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini PC, Orlando P, Di Marzo V (2008) Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 (TRPA1) and melastatin type-8 (TRPM-8). J Pharmacol Exp Ther 325:1007–1015

    PubMed  Google Scholar 

  66. Defalco J, Steiger D, Gustafson A, Emerling DE, Kelly MG, Duncton MA (2010) Oxime derivatives related to AP18: Agonists and antagonists of the TRPA1 receptor. Bioorg Med Chem Lett 20:276–279

    PubMed  CAS  Google Scholar 

  67. Deffontaines Rufin S, Jousse M, Verollet D, Guinet A, Ismael SS, Amarenco G (2010) Cold perception of the bladder during ice water test. Study on 120 patients. Ann Phys Rehabil Med 53:559–567

    PubMed  CAS  Google Scholar 

  68. Del Camino D, Murphy S, Heiry M, Barrett LB, Earley TJ, Cook CA, Petrus MJ, Zhao M, D’Amours M, Deering N, Brenner GJ, Costigan M, Hayward NJ, Chong JA, Fanger CM, Woolf CJ, Patapoutian A, Moran MM (2010) TRPA1 Contributes to Cold Hypersensitivity. J Neurosci 30:15165–15174

    PubMed  Google Scholar 

  69. Deshpande DA, Wang CH, Mcilmoyle EI, Robinett KS, Schillinger RM, An SS, Sham JSK, Ligget SB (2010) Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nat Med 16:1299–1305

    PubMed  CAS  Google Scholar 

  70. Ding Z, Gomez T, Werkheiser JL, Cowan A, Rawls SM (2007) Icilin induces a hyperthermia in rats that is dependent on nitric oxide production and NMDA receptor activation. Eur J Pharmacol 578:201–208

    PubMed  Google Scholar 

  71. Diogenes A, Akopian AN, Hargreaves KM (2007) NGF up-regulates TRPA1: implications for orofacial pain. J Dent Res 86:550–555

    PubMed  CAS  Google Scholar 

  72. Doerner JF, Gisselmann G, Hatt H, Wetzel CH (2007) Transient receptor potential channel A1 is directly gated by calcium ions. J Biol Chem 282:13180–13189

    PubMed  CAS  Google Scholar 

  73. Doihara H, Nozawa K, Kawabata-Shoda E, Kojima R, Yokoyama T, Ito H (2009) TRPA1 agonists delay gastric emptying in rats through serotonergic pathways. Naunyn Schmiedebergs Arch Pharmacol 80:353–357

    Google Scholar 

  74. Dong Y, Shi HL, Shi JR, Wu DZ (2010) Transient receptor potential A1 is involved in cold-induced contraction in the isolated rat colon smooth muscle. Sheng Li Xue Bao 62:349–356

    PubMed  CAS  Google Scholar 

  75. Du S, Araki I, Kobayashi H, Zakoji H, Sawada N, Takeda M (2008) Differential Expression Profile of Cold (TRPA1) and Cool (TRPM8) Receptors in Human Urogenital Organs. Urology 72:450–455

    PubMed  Google Scholar 

  76. Du S, Araki I, Yoshiyama M, Nomura T, Takeda M (2007) Transient receptor potential channel A1 involved in sensory transduction of rat urinary bladder through C-fiber pathway. Urology 70:826–831

    PubMed  Google Scholar 

  77. Dunham JP, Kelly S, Donaldson LF (2008) Inflammation reduces mechanical thresholds in a population of transient receptor potential channel A1-expressing nociceptors in the rat. Eur J Neurosci 27:3151–3160

    PubMed  Google Scholar 

  78. Dunham JP, Leith JL, Lumb BM, Donaldson LF (2010) Transient Receptor Potential Channel A1 and noxious cold responses in rat cutaneous nociceptors. Neuroscience 165:412–1419

    Google Scholar 

  79. Earley S (2012) TRPA1 Channels in the Vasculature. Br J Pharmacol 167:13–22

    PubMed  CAS  Google Scholar 

  80. Earley S, Gonzales AL, Crnich R (2009) Endothelium-Dependent Cerebral Artery Dilation Mediated by TRPA1 and Ca2 + -Activated K + Channels. Circ Res 104:987–U166

    PubMed  CAS  Google Scholar 

  81. Eberhardt MJ, Filipovic MR, Leffler A, de la Roche J, Kistner K, Fleming T, Zimmermann K, Ivanovic-Burmazovic I, Nawroth PP, Bierhaus A, Reeh PW, Sauer SK (2012) Methylglyoxal activates nociceptors through TRPA1 - a possible mechanism of metabolic neuropathies. J Biol Chem 287:28291–28306

    PubMed  CAS  Google Scholar 

  82. Edelmayer RM, Le LN, Yan J, Wei X, Nassini R, Materazzi S, Preti D, Appendino G, Geppetti P, Dodick DW, Vanderah TW, Porreca F, Dussor G (2012) Activation of TRPA1 on dural afferents: A potential mechanism of headache pain. Pain 153:1949–1958

    PubMed  CAS  Google Scholar 

  83. El Karim IA, Linden GJ, Curtis TM, About I, McGahon MK, Irwin CR, Killough SA, Lundy FT (2011) Human Dental Pulp Fibroblasts Express the “Cold-sensing” Transient Receptor Potential Channels TRPA1 and TRPM8. J Endod 37:473–478

    PubMed  Google Scholar 

  84. El Karim IA, Linden GJ, Curtis TM, About I, McGahon MK, Irwin CR, Lundy FT (2011) Human odontoblasts express functional thermo-sensitive TRP channels: Implications for dentin sensitivity. Pain 152:2211–2223

    PubMed  CAS  Google Scholar 

  85. Elitt CM, Malin SA, Koerber HR, Davis BM, Albers KM (2008) Overexpression of artemin in the tongue increases expression of TRPV1 and TRPA1 in trigeminal afferents and causes oral sensitivity to capsaicin and mustard oil. Brain Res 1230:80–90

    PubMed  CAS  Google Scholar 

  86. Elitt CM, McIlwrath SL, Lawson JJ, Malin SA, Molliver DC, Cornuet PK, Koerber HR, Davis BM, Albers KM (2006) Artemin overexpression in skin enhances expression of TRPV1 and TRPA1 in cutaneous sensory neurons and leads to behavioral sensitivity to heat and cold. J Neurosci 26:8578–8587

    PubMed  CAS  Google Scholar 

  87. Engel MA, Leffler A, Niedermirtl F, Babes A, Zimmermann K, Filipovic MR, Izydorczyk I, Eberhardt M, Kichko TI, Mueller-Tribbensee SM, Khalil M, Siklosi N, Nau C, Ivanovic-Burmazovic I, Neuhuber WL, Becker C, Neurath MF, Reeh PW (2011) TRPA1 and Substance P Mediate Colitis in Mice. Gastroenterology 141:1346–1358

    PubMed  CAS  Google Scholar 

  88. Escalera J, von Hehn CA, Bessac BF, Sivula M, Jordt SE (2008) TRPA1 mediates the noxious effects of natural sesquiterpene deterrents. J Biol Chem 283:24136–24144

    PubMed  CAS  Google Scholar 

  89. Fajardo O, Meseguer V, Belmonte C, Viana F (2008) TRPA1 channels mediate cold temperature sensing in mammalian vagal sensory neurons: pharmacological and genetic evidence. J Neurosci 28:7863–7875

    PubMed  CAS  Google Scholar 

  90. Fajardo O, Meseguer V, Belmonte C, Viana F (2008) TRPA1 channels: Novel targets of 1,4-dihydropyridines. Channels (Austin) 2:429–438

    Google Scholar 

  91. Fernandes ES, Russell FA, Spina D, McDougall JJ, Graepel R, Gentry C, Staniland AA, Mountford DM, Keeble JE, Malcangio M, Bevan S, Brain SD (2011) A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor alpha-induced inflammatory hyperalgesia and Freund’s complete adjuvant-induced monarthritis. Arthritis Rheum 63:819–829

    PubMed  CAS  Google Scholar 

  92. Fischer MJ, Leffler A, Niedermirtl F, Kistner K, Eberhardt M, Reeh PW, Nau C (2010) The General Anesthetic Propofol Excites Nociceptors by Activating Trpv1 and Trpa1 Rather Than Gabaa Receptors. J Biol Chem 285:34781–34792

    PubMed  CAS  Google Scholar 

  93. Forster AB, Reeh PW, Messlinger K, Fischer MJ (2009) High concentrations of morphine sensitize and activate mouse dorsal root ganglia via TRPV1 and TRPA1 receptors. Mol Pain 5:17

    PubMed  Google Scholar 

  94. Franck MC, Stenqvist A, Li L, Hao J, Usoskin D, Xu X, Wiesenfeld-Hallin Z, Ernfors P (2011) Essential role of Ret for defining non-peptidergic nociceptor phenotypes and functions in the adult mouse. Eur J Neurosci 33:1385–1400

    PubMed  Google Scholar 

  95. Fujita F, Moriyama T, Higashi T, Shima A, Tominaga M (2007) Methyl p-hydroxybenzoate causes pain sensation through activation of TRPA1 channels. Br J Pharmacol 151:153–160

    PubMed  CAS  Google Scholar 

  96. Fujita T, Uchida K, Moriyama T, Shima A, Shibasaki K, Inada H, Sokabe T, Tominaga M (2008) Intracellular alkalinization causes pain sensation through activation of TRPA1. J Clin Investig 118:4049–4057

    PubMed  CAS  Google Scholar 

  97. Furuta A, Suzuki Y, Hayashi N, Egawa S, Yoshimura N (2012) Transient receptor potential A1 receptor-mediated neural cross-talk and afferent sensitization induced by oxidative stress: Implication for the pathogenesis of interstitial cystitis/bladder pain syndrome. Int J Urol Off J Jpn Urological Assoc 19:429–436

    CAS  Google Scholar 

  98. Garrison SL, Stucky CL (2011) The Dynamic TRPA1 Channel: A Suitable Pharmacological Pain Target? Curr Pharm Biotechnol 12:1689–1697

    PubMed  CAS  Google Scholar 

  99. Garrity PA (2011) Weakly acidic, but strongly irritating: TRPA1 and the activation of nociceptors by cytoplasmic acidification. J Gen Physiol 137:489–491

    PubMed  CAS  Google Scholar 

  100. Gees M, Colsoul B, Nilius B (2010) The Role of Transient Receptor Potential Cation Channels in Ca2+ Signaling. Cold Spring Harb Perspect Biol 2:a003962

    PubMed  CAS  Google Scholar 

  101. Geng J, Liang D, Jiang K, Zhang P (2012) Molecular Evolution of the Infrared Sensory Gene TRPA1 in Snakes and Implications for Functional Studies. PLoS One 6:e28644

    Google Scholar 

  102. Gentry C, Stoakley N, Andersson DA, Bevan S (2010) The roles of iPLA2, TRPM8 and TRPA1 in chemically induced cold hypersensitivity. Mol Pain 6:4

    PubMed  Google Scholar 

  103. Ghiani A, Aina R, Asero R, Bellotto E, Citterio S (2012) Ragweed pollen collected along high-traffic roads shows a higher allergenicity than pollen sampled in vegetated areas. Allergy 67:887–894

    PubMed  CAS  Google Scholar 

  104. Gijsen HJ, Berthelot D, Zaja M, Brone B, Geuens I, Mercken M (2010) Analogues of Morphanthridine and the Tear Gas Dibenz[b, f][1,4]oxazepine (CR) as Extremely Potent Activators of the Human Transient Receptor Potential Ankyrin 1 (TRPA1) Channel. J Med Chem 53:7011–7020

    PubMed  CAS  Google Scholar 

  105. Grace MS, Belvisi MG (2010) TRPA1 receptors in Cough. Pulm Pharmacol Ther 24:286–288

    PubMed  Google Scholar 

  106. Grace M, Birrell MA, Dubuis E, Maher SA, Belvisi MG (2012) Transient receptor potential channels mediate the tussive response to prostaglandin E2 and bradykinin. Thorax 67:891–900

    Google Scholar 

  107. Gracheva EO, Ingolia NT, Kelly YM, Cordero-Morales JF, Hollopeter G, Chesler AT, Sanchez EE, Perez JC, Weissman JS, Julius D (2010) Molecular basis of infrared detection by snakes. Nature 464:1006–1012

    PubMed  CAS  Google Scholar 

  108. Gratzke C, Weinhold P, Reich O, Seitz M, Schlenker B, Stief CG, Andersson KE, Hedlund P (2010) Transient Receptor Potential A1 and Cannabinoid Receptor Activity in Human Normal and Hyperplastic Prostate: Relation to Nerves and Interstitial Cells. Eur Urol 57:902–910

    PubMed  CAS  Google Scholar 

  109. Gregus AM, Doolen S, Dumlao DS, Buczynski MW, Takasusuki T, Fitzsimmons BL, Hua XY, Taylor BK, Dennis EA, Yaksh TL (2012) Spinal 12-lipoxygenase-derived hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors. Proc Natl Acad Sci U S A 109:6721–6726

    PubMed  CAS  Google Scholar 

  110. Gu Q, Lin RL (2010) Heavy metals zinc, cadmium and copper stimulate pulmonary sensory neurons via direct activation of TRPA1. J Appl Physiol 108:891–897

    PubMed  CAS  Google Scholar 

  111. Haas ET, Rowland K, Gautam M (2011) Tooth injury increases expression of the cold sensitive TRP channel TRPA1 in trigeminal neurons. Arch Oral Biol 56:1604–1609

    PubMed  CAS  Google Scholar 

  112. Hamada FN, Rosenzweig M, Kang K, Pulver SR, Ghezzi A, Jegla TJ, Garrity PA (2008) An internal thermal sensor controlling temperature preference in Drosophila. Nature 454:217–220

    PubMed  CAS  Google Scholar 

  113. Hatano N, Itoh Y, Suzuki H, Muraki Y, Hayashi H, Onozaki K, Wood IC, Beech DJ, Muraki K (2012) HIF1alpha switches on TRPA1 gene expression via a hypoxia response element-like motif to modulate cytokine release. J Biol Chemistry in the press

  114. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV (2008) Curcumin: from ancient medicine to current clinical trials. Cellular and Molecular Life Sciences: CMLS 65:1631–1652

    PubMed  CAS  Google Scholar 

  115. Hazari MS, Haykal-Coates N, Winsett DW, Krantz QT, King C, Costa DL, Farraj AK (2011) TRPA1 and Sympathetic Activation Contribute to Increased Risk of Triggered Cardiac Arrhythmias in Hypertensive Rats Exposed to Diesel Exhaust. Environ Heal Perspect 119:951–957

    CAS  Google Scholar 

  116. Hermanstyne TO, Markowitz K, Fan L, Gold MS (2008) Mechanotransducers in rat pulpal afferents. J Dent Res 87:834–838

    PubMed  CAS  Google Scholar 

  117. Hill K, Schaefer M (2007) TRPA1 is differentially modulated by the amphiphatic molecules trinitrophenol and chlorpromazine. J Biol Chem 282:7145–7153

    PubMed  CAS  Google Scholar 

  118. Hill K, Schaefer M (2008) Ultraviolet light and photosensitising agents activate TRPA1 via generation of oxidative stress. Cell Calcium 45:55–164

    Google Scholar 

  119. Hinman A, Chuang H-H, Bautista DM, Julius D (2007) TRP channel activation by reversible covalent modification. Proc Natl Acad Sci (USA) 103:19564–19568

    Google Scholar 

  120. Hjerling-Leffler J, Alqatari M, Ernfors P, Koltzenburg M (2007) Emergence of functional sensory subtypes as defined by transient receptor potential channel expression. J Neurosci 27:2435–2443

    PubMed  CAS  Google Scholar 

  121. Hu H, Bandell M, Petrus MJ, Zhu MX, Patapoutian A (2009) Zinc activates damage-sensing TRPA1 ion channels. Nat Chem Biol 5:183–190

    PubMed  CAS  Google Scholar 

  122. Hu H, Tian J, Zhu Y, Wang C, Xiao R, Herz JM, Wood JD, Zhu MX (2010) Activation of TRPA1 channels by fenamate nonsteroidal anti-inflammatory drugs. Pflugers Arch Europ J Physiol 459:579–592

    CAS  Google Scholar 

  123. Hwang RY, Stearns NA, Tracey WD (2012) The Ankyrin Repeat Domain of the TRPA Protein Painless Is Important for Thermal Nociception but Not Mechanical Nociception. PLoS One 7:e30090

    PubMed  CAS  Google Scholar 

  124. Inoue M, Fujita T, Goto M, Kumamoto E (2012) Presynaptic enhancement by eugenol of spontaneous excitatory transmission in rat spinal substantia gelatinosa neurons is mediated by transient receptor potential A1 channels. Neuroscience 210:403–415

    PubMed  CAS  Google Scholar 

  125. Inoue N, Ito S, Nogawa M, Tajima K, Kyoi T (2012) Etodolac Blocks the Allyl Isothiocyanate-Induced Response in Mouse Sensory Neurons by Selective TRPA1 Activation. Pharmacology 90:47–54

    PubMed  CAS  Google Scholar 

  126. Iwasaki Y, Tanabe M, Kayama Y, Abe M, Kashio M, Koizumi K, Okumura Y, Morimitsu Y, Tominaga M, Ozawa Y, Watanabe T (2009) Miogadial and miogatrial with alpha, beta-unsaturated 1,4-dialdehyde moieties-novel and potent TRPA1 agonists. Life Sci 85:60–69

    PubMed  CAS  Google Scholar 

  127. Jain A, Bronneke S, Kolbe L, Stab F, Wenck H, Neufang G (2011) TRP-channel-specific cutaneous eicosanoid release patterns. Pain 152:2765–2772

    PubMed  CAS  Google Scholar 

  128. Jaquemar D, Schenker T, Trueb B (1999) An ankyrin-like protein with transmembrane domains is specifically lost after oncogenic transformation of human fibroblasts. J Biol Chem 274:7325–7333

    PubMed  CAS  Google Scholar 

  129. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265

    PubMed  CAS  Google Scholar 

  130. Kaji I, Karaki SI, Kuwahara A (2011) Effects of luminal thymol on epithelial transport in human and rat colon. Am J Physiol Gastrointest Liver Physiol 300:G1132–G1143

    PubMed  CAS  Google Scholar 

  131. Kaji I, Yasuoka Y, Karaki SI, Kuwahara A (2012) Activation of TRPA1 by luminal stimuli induces EP4-mediated anion secretion in human and rat colon. Am J Physiol Gastrointest Liver Physiol 302:G690–G701

    PubMed  CAS  Google Scholar 

  132. Kang K, Panzano VC, Chang EC, Ni L, Dainis AM, Jenkins AM, Regna K, Muskavitch MA, Garrity PA (2012) Modulation of TRPA1 thermal sensitivity enables sensory discrimination in Drosophila. Nature 481:76–80

    CAS  Google Scholar 

  133. Kang K, Pulver SR, Panzano VC, Chang EC, Griffith LC, Theobald DL, Garrity PA (2010) Analysis of Drosophila TRPA1 reveals an ancient origin for human chemical nociception. Nature 464:597–U155

    PubMed  CAS  Google Scholar 

  134. Karashima Y, Damann N, Prenen J, Talavera K, Segal A, Voets T, Nilius B (2007) Bimodal action of menthol on the transient receptor potential channel TRPA1. J Neurosci 27:9874–9884

    PubMed  CAS  Google Scholar 

  135. Karashima Y, Prenen J, Meseguer V, Owsianik G, Voets T, Nilius B (2008) Modulation of the transient receptor potential channel TRPA1 by phosphatidylinositol 4,5-biphosphate manipulators. Pflügers Arch Eur J Physiol 457:77–89

    CAS  Google Scholar 

  136. Karashima Y, Prenen J, Talavera K, Janssens A, Voets T, Nilius B (2010) Agonist-Induced Changes in Ca(2+) Permeation through the Nociceptor Cation Channel TRPA1. Biophys J 98:773–783

    PubMed  CAS  Google Scholar 

  137. Karashima Y, Talavera K, Everaerts W, Janssens A, Kwan KY, Vennekens R, Nilius B, Voets T (2009) TRPA1 acts as a cold sensor in vitro and in vivo. Proc Natl Acad Sci U S A 106:1273–1278

    PubMed  CAS  Google Scholar 

  138. Kerstein PC, Del Camino D, Moran MM, Stucky CL (2009) Pharmacological blockade of TRPA1 inhibits mechanical firing in nociceptors. Mol Pain 5:19

    PubMed  Google Scholar 

  139. Kim D, Cavanaugh EJ (2007) Requirement of a soluble intracellular factor for activation of transient receptor potential A1 by pungent chemicals: role of inorganic polyphosphates. J Neurosci 27:6500–6509

    PubMed  CAS  Google Scholar 

  140. Kim D, Cavanaugh E, Simkin D (2009) Inhibition of Transient Receptor Potential A1 by Phosphatidylinositol-4,5-bisphosphate. Amer J Physiol Cell Physiology 295:C92–C99

    Google Scholar 

  141. Kim YS, Jung HK, Kwon TK, Kim CS, Cho JH, Ahn DK, Bae YC (2012) Expression of Transient Receptor Potential Ankyrin 1 in Human Dental Pulp. J Endod 38:1087–1092

    PubMed  Google Scholar 

  142. Kim SH, Lee Y, Akitake B, Woodward OM, Guggino WB, Montell C (2010) Drosophila TRPA1 channel mediates chemical avoidance in gustatory receptor neurons. Proc Natl Acad Sci U S A 107:8440–8445

    PubMed  CAS  Google Scholar 

  143. Kim YS, Son JY, Kim TH, Paik SK, Dai Y, Noguchi K, Ahn DK, Bae YC (2009) Expression of transient receptor potential ankyrin 1 (TRPA1) in the rat trigeminal sensory afferents and spinal dorsal horn. J Comp Neurol 518:687–698

    Google Scholar 

  144. Kimball ES, Prouty SP, Pavlick KP, Wallace NH, Schneider CR, Hornby PJ (2007) Stimulation of neuronal receptors, neuropeptides and cytokines during experimental oil of mustard colitis. Neurogastroenterol Motil 19:390–400

    PubMed  CAS  Google Scholar 

  145. Kindt KS, Viswanath V, Macpherson L, Quast K, Hu H, Patapoutian A, Schafer WR (2007) Caenorhabditis elegans TRPA-1 functions in mechanosensation. Nat Neurosci 10:568–577

    PubMed  CAS  Google Scholar 

  146. Klein AH, Sawyer CM, Zanotto KL, Ivanov MA, Cheung S, Iodi Carstens M, Furrer S, Simons CT, Slack JP, Carstens E (2011) A tingling sanshool derivative excites primary sensory neurons and elicits nocifensive behavior in rats. J Neurophysiol 105:1701–1710

    PubMed  CAS  Google Scholar 

  147. Koch M, Kreutz S, Bottger C, Grabiec U, Ghadban C, Korf HW, Dehghani F (2010) The cannabinoid WIN 55,212-2-mediated protection of dentate gyrus granule cells is driven by CB(1) receptors and modulated by TRPA1 and Ca(v)2.2 channels. Hippocampus 21:554–564

    Google Scholar 

  148. Kohno K, Sokabe T, Tominaga M, Kadowaki T (2010) Honey Bee Thermal/Chemical Sensor, AmHsTRPA, Reveals Neofunctionalization and Loss of Transient Receptor Potential Channel Genes. J Neurosci 30:12219–12229

    PubMed  CAS  Google Scholar 

  149. Koivisto A (2012) Sustained TRPA1 activation in vivo. Acta Physiol 204:248–254

    CAS  Google Scholar 

  150. Kollarik M, Brozmanova M (2009) Cough and gastroesophageal reflux: Insights from animal models. Pulm Pharmacol Ther 22:130–134

    PubMed  CAS  Google Scholar 

  151. Komatsu T, Uchida K, Fujita F, Zhou Y, Tominaga M (2012) Primary alcohols activate human TRPA1 channel in a carbon chain length-dependent manner. Pflugers Archiv Eur J Physiol 463:549–559

    CAS  Google Scholar 

  152. Kondo T, Obata K, Miyoshi K, Sakurai J, Tanaka J, Miwa H, Noguchi K (2009) Transient receptor potential A1 mediates gastric distention-induced visceral pain in rats. Gut 58:1342–1352

    PubMed  CAS  Google Scholar 

  153. Koo JY, Jang Y, Cho H, Lee CH, Jang KH, Chang YH, Shin J, Oh U (2007) Hydroxy-alpha-sanshool activates TRPV1 and TRPA1 in sensory neurons. Eur J Neurosci 26:1139–1147

    PubMed  Google Scholar 

  154. Koseki J, Oshima T, Kondo T, Tomita T, Fukui H, Watari J, Hattori T, Kase Y, Miwa H (2012) Role of transient receptor potential ankyrin 1 in gastric accommodation in conscious guinea pigs. J Pharmacol Exp Ther 341:205–212

    PubMed  CAS  Google Scholar 

  155. Kosugi M, Natatsuka T, Fujita T, Kuroda Y, Kummamoto E (2007) Activation of TRPA1 channel fascilitates excitatory synaptic transmission in substantia gelatinosa neurons of the adult rat spinal cord. J Neurosci 27:4443–4451

    PubMed  CAS  Google Scholar 

  156. Kremeyer B, Lopera F, Cox JJ, Momin A, Rugiero F, Marsh S, Woods CG, Jones NG, Paterson KJ, Fricker FR, Villegas A, Acosta N, Pineda-Trujillo NG, Ramírez JD, Zea J, Burley M-W, Bedoya G, Bennett DLH, Wood JN, Ruiz-Linares A (2010) A Gain-of-Function Mutation in TRPA1 Causes Familial Episodic Pain Syndrome. Neuron 66:671–680

    PubMed  CAS  Google Scholar 

  157. Kunkler PE, Ballard CJ, Oxford GS, Hurley JH (2010) TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation. Pain 152:38–44

    PubMed  Google Scholar 

  158. Kurogi M, Miyashita M, Emoto Y, Kubo Y, Saitoh O (2012) Green Tea Polyphenol Epigallocatechin Gallate Activates TRPA1 in an Intestinal Enteroendocrine Cell Line, STC-1. Chem Senses 37:167–177

    PubMed  CAS  Google Scholar 

  159. Kwan KY, Corey DP (2009) Burning Cold: Involvement of TRPA1 in Noxious Cold Sensation. J Gen Physiol 133:251–256

    PubMed  CAS  Google Scholar 

  160. Kwan KY, Glazer JM, Corey DP, Rice FL, Stucky CL (2009) TRPA1 modulates mechanotransduction in cutaneous sensory neurons. J Neurosci 29:4808–4819

    PubMed  CAS  Google Scholar 

  161. Kwon Y, Shim HS, Wang X, Montell C (2008) Control of thermotactic behavior via coupling of a TRP channel to a phospholipase C signaling cascade. Nat Neorsci 11:871–873

    CAS  Google Scholar 

  162. La JH, Schwartz ES, Gebhart GF (2011) Differences in the expression of transient receptor potential channel V1, transient receptor potential channel A1 and mechanosensitive two pore-domain K(+) channels between the lumbar splanchnic and pelvic nerve innervations of mouse urinary bladder and colon. Neuroscience 186:179–187

    PubMed  CAS  Google Scholar 

  163. Latorre R (2009) Perspectives on TRP Channel Structure and the TRPA1 Puzzle. J Gen Physiol 133:227–229

    PubMed  Google Scholar 

  164. Leamy AW, Shukla P, McAlexander MA, Carr MJ, Ghatta S (2011) Curcumin ((E, E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) activates and desensitizes the nociceptor ion channel TRPA1. Neurosci Lett 503:157–162

    PubMed  CAS  Google Scholar 

  165. Lee SP, Buber T, Yang Q, Cerne R, Corte’s RY, Sprous DG, Bryant RW (2008) Thymol and related alkyl phenols activate the hTRPA1 channel. Br J Pharmacol 153:1739–1749

    PubMed  CAS  Google Scholar 

  166. Lefer DJ (2007) A new gaseous signaling molecule emerges: Cardioprotective role of hydrogen sulfide. Proc Natl Acad Sci U S A 104:17907–17908

    PubMed  CAS  Google Scholar 

  167. Leffler A, Lattrell A, Kronewald S, Niedermirtl F, Nau C (2011) Activation of TRPA1 by membrane permeable local anesthetics. Mol Pain 7:62

    PubMed  CAS  Google Scholar 

  168. Li L, Bhatia M, Moore PK (2006) Hydrogen sulphide–a novel mediator of inflammation? Curr Opin Pharmacol 6:125–129

    PubMed  CAS  Google Scholar 

  169. Liang J, Bi H, Ji W (2010) Involvement of TRPA1 in ET-1-induced pain-like behavior in mice. Neuroreport 21:201–205

    PubMed  CAS  Google Scholar 

  170. Liu T, Ji RR (2012) Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice. Neurosci Bull 28:145–154

    PubMed  CAS  Google Scholar 

  171. Liu K, Samuel M, Ho M, Harrison RK, Paslay JW (2010) NPPB structure-specifically activates TRPA1 channels. Biochem Pharmacol 80:113–121

    PubMed  CAS  Google Scholar 

  172. Macho A, Lucena C, Sancho R, Daddario N, Minassi A, Munoz E, Appendino G (2003) Non-pungent capsaicinoids from sweet pepper. Synthesis and evaluation of their chemopreventive and anticancer potential. Eur J Nutr 42:2–9

    PubMed  CAS  Google Scholar 

  173. Macpherson LJ, Dubin AE, Evans MJ, Marr F, Schultz PG, Cravatt BF, Patapoutian A (2007) Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445:541–545

    PubMed  CAS  Google Scholar 

  174. Macpherson L, Geierstanger BH, Viswanath V, Bandell M, Eid SR, Patapoutian A (2005) The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr Biol 15:929–934

    PubMed  CAS  Google Scholar 

  175. Macpherson LJ, Patapoutian A (2010) Channels: Flies feel your pain. Nat Chem Biol 6:252–253

    PubMed  CAS  Google Scholar 

  176. Macpherson LJ, Xiao B, Kwan KY, Petrus MJ, Dubin AE, Hwang SW, Cravatt B, Corey DP, Patapoutian A (2007) An Ion Channel Essential for Sensing Chemical Damage. J Neurosci 27:11412–11415

    PubMed  CAS  Google Scholar 

  177. Maher M, Ao H, Banke T, Nasser N, Wu N-T, Breitenbucher G, Chaplan SR, Wickenden AD (2008) Activation of TRPA1 by farnesyl thiosalicylic acid, disulfiram and chlordantoin. Mol Pharmacol 73:1225–1234

    PubMed  CAS  Google Scholar 

  178. Maher SA, Dubuis ED, Belvisi MG (2011) G-protein coupled receptors regulating cough. Curr Opin Pharmacol 11:248–253

    PubMed  CAS  Google Scholar 

  179. Maione S, Piscitelli F, Gatta L, Vita D, De Petrocellis L, Palazzo E, De Novellis V, Di Marzo V (2011) Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetised rats through several mechanisms of action. Br J Pharmacol 162:584–596

    PubMed  CAS  Google Scholar 

  180. Malin SA, Molliver DC, Koerber HR, Cornuet P, Frye R, Albers KM, Davis BM (2006) Glial cell line-derived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo. J Neurosci 26:8588–8599

    PubMed  CAS  Google Scholar 

  181. Markowitz K (2009) Pretty painful: Why does tooth bleaching hurt? Med Hypotheses 74:835–840

    PubMed  Google Scholar 

  182. Masamoto Y, Kawabata F, Fushiki T (2009) Intragastric Administration of TRPV1, TRPV3, TRPM8, and TRPA1 Agonists Modulates Autonomic Thermoregulation in Different Manners in Mice. Biosci Biotechnol Biochem 73:1021–1027

    PubMed  CAS  Google Scholar 

  183. Materazzi S, Fusi C, Benemei S, Pedretti P, Patacchini R, Nilius B, Prenen J, Creminon C, Geppetti P, Nassini R (2012) TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism. Pflugers Arch - Eur J Physiol 463:561–569

    CAS  Google Scholar 

  184. Materazzi S, Nassini R, Andre E, Campi B, Amadesi S, Trevisani M, Bunnett NW, Patacchini R, Geppetti P (2008) Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A 105:12045–12050

    PubMed  CAS  Google Scholar 

  185. Matta JA, Cornett PM, Miyares RL, Abe K, Sahibzada N, Ahern GP (2008) General anesthetics activate a nociceptive ion channel to enhance pain and inflammation. Proc Natl Acad Sci (USA) 105:8784–8789

    CAS  Google Scholar 

  186. May D, Baastrup J, Nientit MR, Binder A, Schuenke M, Baron R, Cascorbi I (2012) Differential expression and functionality of TRPA1 genetic variants in conditions of thermal stimulation. J Biol Chem 287:27087–27094

    PubMed  CAS  Google Scholar 

  187. McGaraughty S, Chu KL, Perner RJ, Didomenico S, Kort ME, Kym PR (2010) TRPA1 modulation of spontaneous and mechanically evoked firing of spinal neurons in uninjured, osteoarthritic, and inflamed rats. Mol Pain 6:14

    PubMed  Google Scholar 

  188. McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, Hayward NJ, Chong JA, Julius D, Moran MM, Fanger CM (2007) TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci U S A 104:13525–13530

    PubMed  CAS  Google Scholar 

  189. Menozzi-Smarrito C, Riera CE, Munari C, Le Coutre J, Robert F (2009) Synthesis and Evaluation of New Alkylamides Derived from alpha-Hydroxysanshool, the Pungent Molecule in Szechuan Pepper. J Agric Food Chem 57:1982–1989

    PubMed  CAS  Google Scholar 

  190. Michel MC (2007) Editorial Comment on: Distribution and Function of the Hydrogen Sulfide-Sensitive TRPA1 Ion Channel in Rat Urinary Bladder. Eur Urol 53:399–400

    PubMed  Google Scholar 

  191. Miyamoto T, Dubin AE, Petrus MJ, Patapoutian A (2009) TRPV1 and TRPA1 mediate peripheral nitric oxide-induced nociception in mice. PLoS One 4:e7596

    PubMed  Google Scholar 

  192. Miyamoto R, Otsuguro KI, Ito S (2011) Time- and concentration-dependent activation of TRPA1 by hydrogen sulfide in rat DRG neurons. Neurosci Lett 499:137–142

    PubMed  CAS  Google Scholar 

  193. Mizushima T, Obata K, Katsura H, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Tokunaga A, Mashimo T, Noguchi K (2006) Noxious cold stimulation induces mitogen-activated protein kinase activation in transient receptor potential (TRP) channels TRPA1- and TRPM8-containing small sensory neurons. Neuroscience 140:1337–1348

    PubMed  CAS  Google Scholar 

  194. Morera E, De Petrocellis L, Morera L, Schiano Moriello A, Nalli M, Di Marzo V, Ortar G (2012) Synthesis and biological evaluation of [6]-gingerol analogues as transient receptor potential channel TRPV1 and TRPA1 modulators. Bioorg Med Chem Lett 22:1674–1677

    PubMed  CAS  Google Scholar 

  195. Motter AL, Ahern GP (2012) TRPA1 Is a Polyunsaturated Fatty Acid Sensor in Mammals. PLoS One 7:e38439

    PubMed  CAS  Google Scholar 

  196. Mukhopadhyay I, Gomes P, Aranake S, Shetty M, Karnik P, Damle M, Kuruganti S, Thorat S, Khairatkar-Joshi N (2011) Expression of functional TRPA1 receptor on human lung fibroblast and epithelial cells. J Recept Signal Transduct Res 31:350–358

    PubMed  CAS  Google Scholar 

  197. Nagata K, Duggan A, Kumar G, Garcia-Anoveros J (2005) Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing. J Neurosci 25:4052–4061

    PubMed  CAS  Google Scholar 

  198. Nagatomo K, Ishii H, Yamamoto T, Nakajo K, Kubo Y (2010) The Met268Pro Mutation of Mouse TRPA1 Changes the Effect of Caffeine from Activation to Suppression. Biophys J 99:3609–3618

    PubMed  CAS  Google Scholar 

  199. Nagatomo K, Kubo Y (2008) Caffeine activates mouse TRPA1 channels but suppresses human TRPA1 channels. Proc Natl Acad Sci U S A 105:17373–17378

    PubMed  CAS  Google Scholar 

  200. Namer B, Seifert F, Handwerker HO, Maihofner C (2005) TRPA1 and TRPM8 activation in humans: effects of cinnamaldehyde and menthol. Neuroreport 16:955–959

    PubMed  CAS  Google Scholar 

  201. Narukawa M, Koizumi K, Iwasaki Y, Kubota K, Watanabe T (2010) Galangal Pungent Component, 1′-Acetoxychavicol Acetate, Activates TRPA1. Biosci Biotechnol Biochem 74:1694–1696

    PubMed  CAS  Google Scholar 

  202. Nassenstein C, Kwong KK, Taylor-Clark TE, Kollarik M, Macglashan DW, Braun A, Undem BJ (2008) TRPA1 Expression and Function in Vagal Afferent Nerves Innervating Mouse Lungs. J Physiol 586:1595–1604

    PubMed  CAS  Google Scholar 

  203. Nassini R, Gees M, Harrison S, De Siena G, Materazzi S, Moretto N, Failli P, Preti D, Marchetti N, Cavazzini A, Mancini F, Pedretti P, Nilius B, Patacchini R, Geppetti P (2011) Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation. Pain 152:1621–1631

    PubMed  CAS  Google Scholar 

  204. Nassini R, Materazzi S, Andre E, Sartiani L, Aldini G, Trevisani M, Carnini C, Massi D, Pedretti P, Carini M, Cerbai E, Preti D, Villetti G, Civelli M, Trevisan G, Azzari C, Stokesberry S, Sadofsky L, McGarvey L, Patacchini R, Geppetti P (2010) Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents. FASEB J 24:4904–4916

    PubMed  CAS  Google Scholar 

  205. Nassini R, Materazzi S, Vriens J, Prenen J, Benemei S, De Siena G, la Marca G, Andre E, Preti D, Avonto C, Sadofsky L, Di Marzo V, De Petrocellis L, Dussor G, Porreca F, Taglialatela-Scafati O, Appendino G, Nilius B, Geppetti P (2012) The ‘headache tree’ via umbellulone and TRPA1 activates the trigeminovascular system. Brain 135:376–390

    PubMed  Google Scholar 

  206. Neely GG, Keene AC, Duchek P, Chang EC, Wang QP, Aksoy YA, Rosenzweig M, Costigan M, Woolf CJ, Garrity PA, Penninger JM (2011) TrpA1 Regulates Thermal Nociception in Drosophila. PLoS One 6:e24343

    PubMed  CAS  Google Scholar 

  207. Negri L, Lattanzi R, Giannini E, Canestrelli M, Nicotra A, Melchiorri P (2009) Chapter 11 Bv8/Prokineticins and their Receptors A New Pronociceptive System. Int Rev Neurobiol 85:145–157

    PubMed  CAS  Google Scholar 

  208. Nilius B, Owsianik G (2011) The transient receptor potential family of ion channels. Genome Biol 12:218–229

    PubMed  CAS  Google Scholar 

  209. Nilius B, Owsianik G, Voets T (2008) Transient receptor potential channels meet phosphoinositides. EMBO J 27:2809–2816

    PubMed  CAS  Google Scholar 

  210. Nilius B, Owsianik G, Voets T, Peters JA (2007) Transient Receptor Potential Channels in Disease. Physiol Rev 87:165–217

    PubMed  CAS  Google Scholar 

  211. Nilius B, Prenen J, Owsianik G (2011) Irritating Channels: the case of TRPA1. J Physiol 589:1543–1549

    PubMed  CAS  Google Scholar 

  212. Nozawa K, Kawabata-Shoda E, Doihara H, Kojima R, Okada H, Mochizuki S, Sano Y, Inamura K, Matsushime H, Koizumi T, Yokoyama T, Ito H (2009) TRPA1 regulates gastrointestinal motility through serotonin release from enterochromaffin cells. Proc Natl Acad Sci U S A 106:3408–3413

    PubMed  CAS  Google Scholar 

  213. Numazawa S, Takase M, Ahiko T, Ishii M, Shimizu S, Yoshida T (2012) Possible Involvement of Transient Receptor Potential Channels in Electrophile-Induced Insulin Secretion from RINm5F Cells. Biol Pharm Bull 35:346–354

    PubMed  CAS  Google Scholar 

  214. Ogawa H, Takahashi K, Miura S, Imagawa T, Saito S, Tominaga M, Ohta T (2012) H(2)S Functions as a Nociceptive Messenger Through Transient Receptor Potential Ankyrin 1 (Trpa1) Activation. Neuroscience 218:335–343

    PubMed  CAS  Google Scholar 

  215. Okubo K, Matsumura M, Kawaishi Y, Aoki Y, Matsunami M, Okawa Y, Sekiguchi F, Kawabata A (2012) Hydrogen sulfide-induced mechanical hyperalgesia and allodynia require activation of both Ca(v) 3.2 and TRPA1 channels in mice. Br J Pharmacol 166:1738–1743

    PubMed  CAS  Google Scholar 

  216. Okumura Y, Narukawa M, Iwasaki Y, Ishikawa A, Matsuda H, Yoshikawa M, Watanabe T (2010) Activation of TRPV1 and TRPA1 by Black Pepper Components. Biosci Biotechnol Biochem 74:1068–1072

    PubMed  CAS  Google Scholar 

  217. Panzano VC, Kang K, Garrity PA (2010) Infrared Snake Eyes: TRPA1 and the Thermal Sensitivity of the Snake Pit Organ. Sci Signal 3:pe22

    PubMed  Google Scholar 

  218. Patacchini R, Santicioli P, Giuliani S, Maggi CA (2005) Pharmacological investigation of hydrogen sulfide (H2S) contractile activity in rat detrusor muscle. Eur J Pharmacol 509:171–177

    PubMed  CAS  Google Scholar 

  219. Patapoutian A, Peier AM, Story GM, Viswanath V (2003) ThermoTRP channels and beyond: mechanisms of temperature sensation. Nat Rev Neurosci 4:529–539

    PubMed  CAS  Google Scholar 

  220. Patil MJ, Belugin S, Akopian AN (2011) Chronic alteration in phosphatidylinositol 4,5-biphosphate levels regulates capsaicin and mustard oil responses. J Neurosci Res 89:945–954

    PubMed  CAS  Google Scholar 

  221. Patil MJ, Jeske NA, Akopian AN (2010) TRPV1 regulates activation and modulation of TRPA1 by Ca2+. Neuroscience 171:1109–1119

    PubMed  CAS  Google Scholar 

  222. Patil M, Patwardhan A, Salas MM, Hargreaves KM, Akopian AN (2011) Cannabinoid receptor antagonists AM251 and AM630 activate TRPA1 in sensory neurons. Neuropharmacology 61:778–788

    PubMed  CAS  Google Scholar 

  223. Pecze L, Pelsoczi P, Kecskés M, Winter Z, Papp A, Kaszá K, Letoha L, Vizler C, Oláh Z (2009) Resiniferatoxin Mediated Ablation of TRPV1+ Neurons Removes TRPA1 as Well. Can J Neurol Sci 36:234–241

    PubMed  Google Scholar 

  224. Pertovaara A, Koivisto A (2011) TRPA1 ion channel in the spinal dorsal horn as a therapeutic target in central pain hypersensitivity and cutaneous neurogenic inflammation. Eur J Pharmacol 666:1–4

    PubMed  CAS  Google Scholar 

  225. Peterlin Z, Chesler A, Firestein S (2007) A painful Trp can be a bonding experience. Neuron 53:635–638

    PubMed  CAS  Google Scholar 

  226. Peyrot des Gachons C, Uchida K, Bryant B, Shima A, Sperry JB, Dankulich-Nagrudny L, Tominaga M, Smith AB 3rd, Beauchamp GK, Breslin PA (2011) Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal. J Neurosci 31:999–1009

    PubMed  Google Scholar 

  227. Piao L-H, Fujita T, Jiang C-Y, Liu T, Yue HY, Nakatsuka T, Kumamoto E (2009) TRPA1 activation by lidocaine in nerve terminals results in glutamate release increase. Biochem Biophys Res Commun 379:980–984

    PubMed  CAS  Google Scholar 

  228. Pollastro F, Taglialatela-Scafati O, Allara M, Munoz E, Di Marzo V, De Petrocellis L, Appendino G (2011) Bioactive Prenylogous Cannabinoid from Fiber Hemp (Cannabis sativa). J Nat Prod 74:2019–2022

    PubMed  CAS  Google Scholar 

  229. Poole DP, Pelayo JC, Cattaruzza F, Kuo YM, Gai G, Chiu JV, Bron R, Furness JB, Grady EF, Bunnett NW (2011) Transient Receptor Potential Ankyrin 1 is Expressed by Inhibitory Motoneurons of the Mouse Intestine. Gastroenterology 141:565–U656

    PubMed  CAS  Google Scholar 

  230. Pozsgai G, Bodkin JV, Graepel R, Bevan S, Andersson DA, Brain SD (2010) Evidence for the Pathophysiological Relevance of Trpa1 Receptors in the Cardiovascular System in Vivo. Cardiovasc Res 87:760–768

    PubMed  CAS  Google Scholar 

  231. Pozsgai G, Hajna Z, Bagoly T, Boros M, Kemeny A, Materazzi S, Nassini R, Helyes Z, Szolcsanyi J, Pinter E (2012) The role of transient receptor potential ankyrin 1 (TRPA1) receptor activation in hydrogen-sulphide-induced CGRP-release and vasodilation. Eur J Pharmacol 689:56–64

    PubMed  CAS  Google Scholar 

  232. Prober DA, Zimmerman S, Myers BR, McDermott BM Jr, Kim SH, Caron S, Rihel J, Solnica-Krezel L, Julius D, Hudspeth AJ, Schier AF (2008) Zebrafish TRPA1 channels are required for chemosensation but not for thermosensation or mechanosensory hair cell function. J Neurosci 28:10102–10110

    PubMed  CAS  Google Scholar 

  233. Qian X, Francis M, Solodushko V, Earley S, Taylor MS (2012) Recruitment of Dynamic Endothelial Ca(2+) Signals by the TRPA1 Channel Activator AITC in Rat Cerebral Arteries. Microcirculation in the press

  234. Raemdonck K, de Alba J, Birrell MA, Grace M, Maher SA, Irvin CG, Fozard JR, O’Byrne PM, Belvisi MG (2011) A role for sensory nerves in the late asthmatic response. Thorax 67:19–25

    PubMed  Google Scholar 

  235. Rawls SM, Benamar K (2011) Effects of opioids, cannabinoids, and vanilloids on body temperature. Front Biosci (Schol Ed) 3:822–845

    Google Scholar 

  236. Rech JC, Eckert WA, Maher MP, Banke T, Bhattacharya A, Wickenden AD (2011) Recent advances in the biology and medicinal chemistry of TRPA1. Future Med Chem 2:843–858

    Google Scholar 

  237. Riera CE, Menozzi-Smarrito C, Affolter M, Michlig S, Munari C, Robert F, Vogel H, Simon SA, le Coutre J (2009) Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels. Brit J Pharm 157:1398–1409

    CAS  Google Scholar 

  238. Rodrigues MR, Kanazawa LK, Neves TL, Silva CF, Horst H, Pizzolatti MG, Santos AR, Baggio CH, Werner MF (2011) Antinociceptive and anti-inflammatory potential of extract and isolated compounds from the leaves of Salvia officinalis in mice. J Ethnopharmacol 139:519–526

    PubMed  Google Scholar 

  239. Rubin BK (2007) Mucolytics, expectorants, and mucokinetic medications. Respir Care 52:859–865

    PubMed  Google Scholar 

  240. Ruparel NB, Patwardhan AM, Akopian AN, Hargreaves KM (2011) Desensitization of TRPA1 by the TRPV1-selective cannabinoid arachidonoly-2chloroethanolamine (ACEA). Mol Pharmacol 80:117–123

    PubMed  CAS  Google Scholar 

  241. Sadofsky LR, Boa AN, Maher SA, Birrell MA, Belvisi MG, Morice AH (2010) TRPA1 is activated by direct addition of cysteine residues to the N-hydroxysuccinyl esters of acrylic and cinnamic acids. Pharmacol Res 63:30–36

    PubMed  Google Scholar 

  242. Saito S, Nakatsuka K, Takahashi K, Fukuta N, Imagawa T, Ohta T, Tominaga M (2012) Analysis of Transient Receptor Potential Ankyrin 1 (TRPA1) in Frogs and Lizards Illuminates Both Nociceptive Heat and Chemical Sensitivities and Coexpression with TRP vanilloid 1 (TRPV1) in Ancestral Vertebrates. J Biol Chem 287:30743–30754

    PubMed  CAS  Google Scholar 

  243. Salas MM, Hargreaves KM, Akopian AN (2009) TRPA1-mediated responses in trigeminal sensory neurons: interaction between TRPA1 and TRPV1. Europ J Neurosci 29:1568–1578

    Google Scholar 

  244. Samad A, Sura L, Benedikt J, Ettrich R, Minofar B, Teisinger J, Vlachova V (2011) The C-terminal basic residues contribute to the chemical and voltage-dependent activation of TRPA1. Biochem J 433:197–204

    PubMed  CAS  Google Scholar 

  245. Saunders CJ, Silver WL (2008) The Respiratory Response of TRPV1 Knockout Mice to Trigeminal Irritants. Chem Senses 33:S104–S104

    Google Scholar 

  246. Sawada Y, Hosokawa H, Hori A, Matsumura K, Kobayashi S (2007) Cold sensitivity of recombinant TRPA1 channels. Brain Res 1160:39–46

    PubMed  CAS  Google Scholar 

  247. Sawada Y, Hosokawa H, Matsumura K, Kobayashi S (2008) Activation of transient receptor potential ankyrin 1 by hydrogen peroxide. Eur J Neurosci 27:1131–1142

    PubMed  Google Scholar 

  248. Schmidt M, Dubin AE, Petrus MJ, Earley TJ, Patapoutian A (2009) Nociceptive Signals Induce Trafficking of TRPA1 to the Plasma Membrane. Neuron 64:498–509

    PubMed  CAS  Google Scholar 

  249. Schwartz ES, Christianson JA, Chen X, La JH, Davis BM, Albers KM, Gebhart GF (2011) Synergistic Role of TRPV1 and TRPA1 in Pancreatic Pain and Inflammation. Gastroenterology 140:140

    Google Scholar 

  250. Sculptoreanu A, Kullmann FA, Artim DE, Bazley FA, Schopfer F, Woodcock S, Freeman BA, de Groat W (2010) Nitro-oleic acid inhibits firing and activates TRPV1- and TRPA1-mediated inward currents in DRG neurons from adult male rats. J Pharmacol Exp Ther 333:883–895

    PubMed  CAS  Google Scholar 

  251. Senatore S, Rami Reddy V, Semeriva M, Perrin L, Lalevee N (2010) Response to Mechanical Stress Is Mediated by the TRPA Channel Painless in the Drosophila Heart. PLoS Genet 6:e1001088, pii

    PubMed  Google Scholar 

  252. Shigetomi E, Tong X, Kwan KY, Corey DP, Khakh BS (2012) TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3. Nat Neorsci 15:70–80

    CAS  Google Scholar 

  253. Shintaku K, Uchida K, Suzuki Y, Yiming Z, Fushiki T, Watanabe T, Yazawa S, Tominaga M (2012) Activation of TRPA1 by a non-pungent capsaicin-like compound, capsiate. Br J Pharmacol 165:1476–1486

    PubMed  CAS  Google Scholar 

  254. Silva CR, Oliveira SM, Rossato MF, Dalmolin GD, Guerra GP, Prudente AD, Cabrini DA, Otuki MF, Andre E, Ferreira J (2011) The involvement of TRPA1 channel activation in the inflammatory response evoked by topical application of cinnamaldehyde to mice. Life Sci 88:1077–1087

    PubMed  CAS  Google Scholar 

  255. Sisignano M, Park CK, Angioni C, Zhang DD, von Hehn C, Cobos EJ, Ghasemlou N, Xu ZZ, Kumaran V, Lu R, Grant A, Fischer MJ, Schmidtko A, Reeh P, Ji RR, Woolf CJ, Geisslinger G, Scholich K, Brenneis C (2012) 5,6-EET Is Released upon Neuronal Activity and Induces Mechanical Pain Hypersensitivity via TRPA1 on Central Afferent Terminals. J Neurosci 32:6364–6372

    PubMed  CAS  Google Scholar 

  256. Smith MP, Beacham D, Ensor E, Koltzenburg M (2004) Cold-sensitive, menthol-insensitive neurons in the murine sympathetic nervous system. Neuroreport 15:1399–1403

    PubMed  Google Scholar 

  257. Staruschenko A, Jeske NA, Akopian AN (2010) Contribution of TRPV1-TRPA1 interaction to the single-channel properties of the TRPA1 channel. J Biol Chem 85:15167–15177

    Google Scholar 

  258. Stepanyan RS, Indzhykulian AA, Velez-Ortega AC, Boger ET, Steyger PS, Friedman TB, Frolenkov GI (2011) TRPA1-Mediated Accumulation of Aminoglycosides in Mouse Cochlear Outer Hair Cells. J Assoc Res Otolaryngol Otolaryngol JARO 12:729–740

    Google Scholar 

  259. Stokes A, Wakano C, Koblan-Huberson M, Adra CN, Fleig A, Turner H (2006) TRPA1 is a substrate for de-ubiquitination by the tumor suppressor CYLD. Cell Signal 18:1584–1594

    PubMed  CAS  Google Scholar 

  260. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, Patapoutian A (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–829

    PubMed  CAS  Google Scholar 

  261. Streng T, Axelsson HE, Hedlund P, Andersson DA, Jordt SE, Bevan S, Andersson KE, Hogestatt ED, Zygmunt PM (2008) Distribution and Function of the Hydrogen Sulfide-Sensitive TRPA1 Ion Channel in Rat Urinary Bladder. Eur Urol 53:391–399

    PubMed  CAS  Google Scholar 

  262. Sun B, Bang SI, Jin YH (2009) Transient receptor potential A1 increase glutamate release on brain stem neurons. Neuroreport 20:1002–1006

    PubMed  CAS  Google Scholar 

  263. Sun X, Ku DD (2006) Allicin in garlic protects against coronary endothelial dysfunction and right heart hypertrophy in pulmonary hypertensive rats. Am J Physiol Heart Circ Physiol 291:H2431–H2438

    PubMed  CAS  Google Scholar 

  264. Sun Y, Lei L, Ben-Shaharb Y, Jacobs JS, Eber DF, Welsh W, Welsh MJ (2009) TRPA channels distinguish gravity sensing from hearing in Johnston’s organ. Proc Nat Am Acad 106:13606–13611

    CAS  Google Scholar 

  265. Sura L, Zima V, Marsakova L, Hynkova A, Barvik I, Vlachova V (2012) C-terminal acidic cluster is involved in the Ca2 + -induced regulation of the human TRPA1 channel. J Biol Chem 287:18067–18077

    PubMed  CAS  Google Scholar 

  266. Sviderskaya EV, Easty DJ, Lawrence MA, Sanchez DP, Negulyaev YA, Patel RH, Anand P, Korchev YE, Bennett DC (2009) Functional neurons and melanocytes induced from immortal lines of postnatal neural crest-like stem cells. FASEB J 23:3179–3192

    PubMed  CAS  Google Scholar 

  267. Szabo C (2007) Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 6:917–935

    PubMed  CAS  Google Scholar 

  268. Taglialatela-Scafati O, Pollastro F, Minassi A, Chianese G, De Petrocellis L, Di Marzo V, Appendino G (2012) Sesquiterpenoids from common ragweed (Ambrosia artemisiifolia L.) an invasive biological polluter. Eur J Org Chem in press; doi:10.1002/ejoc.201200650

  269. Takahashi N, Kuwaki T, Kiyonaka S, Numata T, Kozai D, Mizuno Y, Yamamoto S, Naito S, Knevels E, Carmeliet P, Oga T, Kaneko S, Suga S, Nokami T, Yoshida JI, Mori Y (2011) TRPA1 underlies a sensing mechanism for O(2). Nat Chem Biol 28:701–711

    Google Scholar 

  270. Takahashi N, Mizuno Y, Kozai D, Yamamoto S, Kiyonaka S, Shibata T, Uchida K, Mori Y (2008) Molecular characterization of TRPA1 channel activation by cysteine-reactive inflammatory mediators. Channels (Austin) 2:287–298

    Google Scholar 

  271. Takahashi N, Mori Y (2011) TRP Channels as Sensors and Signal Integrators of Redox Status Changes. Front Pharmacol 2:58

    PubMed  CAS  Google Scholar 

  272. Takumida M, Ishibashi T, Hamamoto T, Hirakawa K, Anniko M (2008) Expression of transient receptor potential channel melastin (TRPM) 1-8 and TRPA1 (ankyrin) in mouse inner ear. Acta Otolaryngol 129:1050–1060

    Google Scholar 

  273. Talavera K, Gees M, Karashima Y, Meseguer VM, Vanoirbeek JA, Damann N, Everaerts W, Benoit M, Janssens A, Vennekens R, Viana F, Nemery B, Nilius B, Voets T (2009) Nicotine activates the chemosensory cation channel TRPA1. Nat Neorsci 12:1293–1299

    CAS  Google Scholar 

  274. Taylor-Clark TE, Ghatta S, Bettner W, Undem BJ (2009) Nitrooleic acid, an Endogenous Product of Nitrative Stress, Activates Nociceptive Sensory Nerves via the Direct Activation of TRPA1. Mol Pharmacol 75:820–829

    PubMed  CAS  Google Scholar 

  275. Taylor-Clark TE, Kiros F, Carr MJ, McAlexander MA (2009) Transient Receptor Potential Ankyrin 1 Mediates Toluene Diisocyanate-Evoked Respiratory Irritation. Am J Respir Cell Mol Biol 40:756–762

    PubMed  CAS  Google Scholar 

  276. Taylor-Clark TE, McAlexander MA, Nassenstein C, Sheardown SA, Wilson S, Thornton J, Carr MJ, Undem BJ (2008) Relative contributions of TRPA1 and TRPV1 channels in the activation of vagal bronchopulmonary C-fibres by the endogenous autocoid 4-oxononenal. J Physiol (Lond) 586:3447–3459

    CAS  Google Scholar 

  277. Taylor-Clark TE, Nassenstein C, McAlexander MA, Undem BJ (2008) TRPA1: A potential target for anti-tussive therapy. Pulm Pharmacol Ther 22:71–74

    PubMed  Google Scholar 

  278. Taylor-Clark TE, Undem BJ (2010) Ozone activates airway nerves via the selective stimulation of TRPA1 ion channels. J Physiol (Lond) 588:423–433

    CAS  Google Scholar 

  279. Taylor-Clark TE, Undem BJ (2011) Sensing pulmonary oxidative stress by lung vagal afferents. Respir Physiol Neurobiol 178:406–413

    PubMed  CAS  Google Scholar 

  280. Taylor-Clark TE, Undem BJ, Macglashan DW Jr, Ghatta S, Carr MJ, McAlexander MA (2008) Prostaglandin-induced activation of nociceptive neurons via direct interaction with transient receptor potential A1 (TRPA1). Mol Pharmacol 73:274–281

    PubMed  CAS  Google Scholar 

  281. Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R, Campi B, Imamachi N, Andre E, Patacchini R, Cottrell GS, Gatti R, Basbaum AI, Bunnett NW, Julius D, Geppetti P (2007) 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A 104:13519–13524

    PubMed  CAS  Google Scholar 

  282. Uchida K, Miura Y, Nagai M, Tominaga M (2012) Isothiocyanates from Wasabia japonica activate transient receptor potential ankyrin 1 channel. Chem Senses in the press

  283. Undem BJ, Carr MJ (2010) Targeting primary afferent nerves for novel antitussive therapy. Chest 137:177–184

    PubMed  CAS  Google Scholar 

  284. Uta D, Furue H, Pickering AE, Harunor Rashid M, Mizuguchi-Takase H, Katafuchi T, Imoto K, Yoshimura M (2010) TRPA1-expressing primary afferents synapse with a morphologically identified subclass of substantia gelatinosa neurons in the adult rat spinal cord. Eur J Neurosci 31:1960–1973

    PubMed  Google Scholar 

  285. Vilceanu D, Stucky CL (2010) TRPA1 Mediates Mechanical Currents in the Plasma Membrane of Mouse Sensory Neurons. PLoS One 5:e12177

    PubMed  Google Scholar 

  286. Vriens J, Appendino G, Nilius B (2009) Pharmacology of vanilloid transient receptor potential cation channels Trpv. Mol Pharmacol 75:1262–1279

    PubMed  CAS  Google Scholar 

  287. Wang YY, Chang RB, Allgood SD, Silver WL, Liman ER (2011) A TRPA1-dependent mechanism for the pungent sensation of weak acids. J Gen Physiol 137:493–505

    PubMed  CAS  Google Scholar 

  288. Wang YY, Chang RB, Liman ER (2010) TRPA1 Is a Component of the Nociceptive Response to CO2. J Neurosci 30:12958–12963

    PubMed  CAS  Google Scholar 

  289. Wang YY, Chang RB, Waters HN, McKemy DD, Liman ER (2008) The nociceptor ion channel TRPA1 is potentiated and inactivated by permeating calcium ions. J Biol Chem 283:32691–32703

    PubMed  CAS  Google Scholar 

  290. Wang L, Cvetkov TL, Chance MR, Moiseenkova-Bell VY (2012) Identification of in vivo disulfide conformation of the TRPA1 ion channel. J Biol Chem 287:6169–6176

    PubMed  CAS  Google Scholar 

  291. Wang S, Dai Y, Fukuoka T, Yamanaka H, Kobayashi K, Obata K, Cui X, Tominaga M, Noguchi K (2008) Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1: a molecular mechanism of inflammatory pain. Brain 131:1241–1251

    PubMed  Google Scholar 

  292. Wang K, Guo Y, Wang F, Wang Z (2011) Drosophila TRPA Channel Painless Inhibits Male-Male Courtship Behavior through Modulating Olfactory Sensation. PLoS One 6:e25890

    PubMed  CAS  Google Scholar 

  293. Wang S, Lee J, Ro JY, Chung MK (2012) Warmth suppresses and desensitizes damage-sensing ion channel TRPA1. Mol Pain 8:22

    PubMed  CAS  Google Scholar 

  294. Wang G, Qiu YT, Lu T, Kwon HW, Jason Pitts R, Van Loon JJ, Takken W, Zwiebel LJ (2009) Anopheles gambiae TRPA1 is a heat-activated channel expressed in thermosensitive sensilla of female antennae. Eur J Neurosci 30:967–974

    PubMed  Google Scholar 

  295. Wang K, Zhao X, Chan S, Cil O, He N, Song X, Paterson AD, Pei Y (2009) Evidence for Pathogenicity of Atypical Splice Mutations in Autosomal Dominant Polycystic Kidney Disease. Clin J Am Soc Nephrol 4:442–449

    PubMed  CAS  Google Scholar 

  296. Wei H, Hamalainen MM, Saarnilehto M, Koivisto A, Pertovaara A (2009) Attenuation of Mechanical Hypersensitivity by an Antagonist of the TRPA1 Ion Channel in Diabetic Animals. Anesthesiology 111:147–154

    PubMed  CAS  Google Scholar 

  297. Wei H, Karimaa M, Korjamo T, Koivisto A, Pertovaara A (2012) Transient Receptor Potential Ankyrin 1 Ion Channel Contributes to Guarding Pain and Mechanical Hypersensitivity in a Rat Model of Postoperative Pain. Anesthesiology 117:137–148

    PubMed  CAS  Google Scholar 

  298. Wei H, Koivisto A, Saarnilehto M, Chapman H, Kuokkanen K, Hao B, Huang JL, Wang YX, Pertovaara A (2011) Spinal transient receptor potential ankyrin 1 channel contributes to central pain hypersensitivity in various pathophysiological conditions in the rat. Pain 152:582–591

    PubMed  CAS  Google Scholar 

  299. Weller K, Reeh PW, Sauer SK (2011) TRPV1, TRPA1, and CB1 in the isolated vagus nerve - Axonal chemosensitivity and control of neuropeptide release. Neuropeptides 45:391–400

    PubMed  CAS  Google Scholar 

  300. White BJ, Smith PA, Dunn WR (2012) Hydrogen sulphide-mediated vasodilatation involves the release of neurotransmitters from sensory nerves in pressurized mesenteric small arteries isolated from rats. Br J Pharmacol in the press

  301. Wilkinson JD, Kendall DA, Ralevic V (2007) Delta(9)-Tetrahydrocannabinol inhibits electrically-evoked CGRP release and capsaicin-sensitive sensory neurogenic vasodilatation in the rat mesenteric arterial bed. Br J Pharmacol 152:709–716

    PubMed  CAS  Google Scholar 

  302. Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN, Dong X, Bautista DM (2011) TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neorsci 14:595–602

    CAS  Google Scholar 

  303. Wood H (2010) Pain: new familial pain syndrome caused by TRPA1 mutation. Nat Rev Neurol 6:412

    PubMed  Google Scholar 

  304. Wu LJ, Sweet TB, Clapham DE (2010) International Union of Basic and Clinical Pharmacology. LXXVI. Current Progress in the Mammalian TRP Ion Channel Family. Pharmacol Rev 62:381–404

    PubMed  CAS  Google Scholar 

  305. Xiao B, Dubin AE, Bursulaya B, Viswanath V, Jegla TJ, Patapoutian A (2008) Identification of the Transmembrane Domain Five as a Critical Molecular Determinant of Menthol Sensitivity in Mammalian TRPA1 Channels. J Neurosci 28:9640–9651

    PubMed  CAS  Google Scholar 

  306. Xu H, Delling M, Jun JC, Clapham DE (2006) Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels. Nat Neorsci 9:628–635

    CAS  Google Scholar 

  307. Xu J, Sornborger AT, Lee JK, Shen P (2008) Drosophila TRPA channel modulates sugar-stimulated neural excitation, avoidance and social response. Nat Neurosci 11:676–682

    PubMed  CAS  Google Scholar 

  308. Yang J, Li Y, Zuo X, Zhen Y, Yu Y, Gao L (2008) Transient receptor potential ankyrin-1 participates in visceral hyperalgesia following experimental colitis. Neurosci Lett 440:237–241

    PubMed  CAS  Google Scholar 

  309. Yassaka RT, Inagaki H, Fujino T, Nakatani K, Kubo T, Mikoshiba K (2010) Enhanced Activation of the Transient Receptor Potential Channel TRPA1 by Ajoene, an Allicin Derivative. Neurosci Res 66:99–105

    PubMed  CAS  Google Scholar 

  310. Ye Y, Dang D, Zhang J, Viet CT, Lam DK, Dolan J, Gibbs J, Schmidt BL (2011) Nerve growth factor links oral cancer progression, pain, and cachexia. Mol Cancer Ther 10:1667–1676

    PubMed  CAS  Google Scholar 

  311. Yokoyama S, Altun A, Denardo DF (2011) Molecular Convergence of Infrared Vision in Snakes. Mol Biol Evol 28:45–48

    PubMed  CAS  Google Scholar 

  312. Yokoyama T, Ohbuchi T, Saito T, Sudo Y, Fujihara H, Minami K, Nagatomo T, Uezono Y, Ueta Y (2011) Allyl isothiocyanates and cinnamaldehyde potentiate miniature excitatory postsynaptic inputs in the supraoptic nucleus in rats. Eur J Pharmacol 655:31–37

    PubMed  CAS  Google Scholar 

  313. Yoshida N, Kobayashi K, Yu L, Wang S, Na R, Yamamoto S, Noguchi K, Dai Y (2011) Inhibition of TRPA1 channel activity in sensory neurons by the glial cell line-derived neurotrophic factor family member, artemin. Mol Pain 7:41

    PubMed  CAS  Google Scholar 

  314. Yu S, Gao G, Peterson BZ, Ouyang A (2009) TRPA1 in Mast Cell Activation-induced Long-lasting Mechanical Hypersensitivity of Vagal Afferent C fibers in Guinea Pig Esophagus. Am J Physiol Gastrointest Liver Physiol 297:G34–G42

    PubMed  CAS  Google Scholar 

  315. Yu S, Ouyang A (2008) TRPA1 in Bradykinin-induced Mechano-hypersensitivity of Vagal C Fibers in Guinea Pig Esophagus. Am J Physiol Gastrointest Liver Physiol 296:G255–G265

    PubMed  Google Scholar 

  316. Yu YB, Yang J, Zuo XL, Gao LJ, Wang P, Li YQ (2010) Transient Receptor Potential Vanilloid-1 (TRPV1) and Ankyrin-1 (TRPA1) Participate in Visceral Hyperalgesia in Chronic Water Avoidance Stress Rat Model. Neurochem Res 35:797–803

    PubMed  CAS  Google Scholar 

  317. Zanotto K, Merrill AW, Iodi Carstens M, Carstens E (2007) Neurons in superficial trigeminal subnucleus caudalis responsive to oral cooling, menthol and other irritant stimuli. J Neurophysiol 97:966–978

    PubMed  CAS  Google Scholar 

  318. Zayats V, Samad A, Minofar B, Roelofs KE, Stockner T, Ettrich R (2012) Regulation of the transient receptor potential channel TRPA1 by its N-terminal ankyrin repeat domain. J Mol Model in the press

  319. Zhang XF, Chen J, Faltynek CR, Moreland RB, Neelands TR (2008) Transient receptor potential A1 mediates an osmotically activated ion channel. Eur J Neurosci 27:605–611

    PubMed  Google Scholar 

  320. Zhang H, Wickley PJ, Sinha S, Bratz IN, Damron DS (2011) Propofol Restores Transient Receptor Potential Vanilloid Receptor Subtype-1 Sensitivity via Activation of Transient Receptor Potential Ankyrin Receptor Subtype-1 in Sensory Neurons. Anesthesiology 114:1169–1179

    PubMed  CAS  Google Scholar 

  321. Zhong L, Bellemer A, Yan H, Honjo K, Robertson J, Hwang RY, Pitt GS, Tracey WD (2012) Thermosensory and Nonthermosensory Isoforms of Drosophila melanogaster TRPA1 Reveal Heat-Sensor Domains of a ThermoTRP Channel. Cell Rep 1:43–55

    PubMed  CAS  Google Scholar 

  322. Zhong J, Minassi A, Prenen J, Taglialatela-Scafati O, Appendino G, Nilius B (2011) Umbellulone modulates TRP channels. Pflügers Arch Eur J Physiol 462:861–870

    CAS  Google Scholar 

  323. Zhong J, Pollastro F, Prenen J, Zhu Z, Appendino G, Nilius B (2011) Ligustilide: a novel TRPA1 modulator. Pflugers Arch Eur J Physiol 462:841–849

    CAS  Google Scholar 

  324. Zhou Y, Sun B, Li Q, Luo P, Dong L, Rong W (2011) Sensitivity of bronchopulmonary receptors to cold and heat mediated by transient receptor potential cation channel subtypes in an ex vivo rat lung preparation. Respir Physiol Neurobiol 177:327–332

    PubMed  CAS  Google Scholar 

  325. Zurborg S, Yurgionas B, Jira JA, Caspani O, Heppenstall PA (2007) Direct activation of the ion channel TRPA1 by Ca(2+). Nat Neorsci 10:277–279

    CAS  Google Scholar 

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Acknowldegments

We thank the members of the Laboratory of Ion Channel Research for helpful discussions. This work was supported by grants from the Belgian Federal Government (IUAP P5/05), the Research Foundation-Flanders (G.0172.03, G.0565.07 and G.0149.03), and the Research Council of the KU Leuven (GOA 2004/07 and EF/95/010).

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Correspondence to Bernd Nilius.

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Nilius, B., Appendino, G. & Owsianik, G. The transient receptor potential channel TRPA1: from gene to pathophysiology. Pflugers Arch - Eur J Physiol 464, 425–458 (2012). https://doi.org/10.1007/s00424-012-1158-z

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  • DOI: https://doi.org/10.1007/s00424-012-1158-z

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