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Pflügers Archiv - European Journal of Physiology

, Volume 464, Issue 5, pp 425–458 | Cite as

The transient receptor potential channel TRPA1: from gene to pathophysiology

  • Bernd Nilius
  • Giovanni Appendino
  • Grzegorz Owsianik
Invited Review

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.

Keywords

Transient receptor potential Ca2+ channels Ankyrin repeat domain Nociception Mechano-sensing Channeloparthies 

Notes

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).

References

  1. 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 31:435–444PubMedGoogle Scholar
  2. 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 2:551PubMedGoogle Scholar
  3. 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 28:2485–2494PubMedGoogle Scholar
  4. 4.
    Andersson DA, Gentry C, Moss S, Bevan S (2009) Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn2+. Proc Natl Acad Sci (USA) 106:8374–8379Google Scholar
  5. 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 106:1114–1127PubMedGoogle Scholar
  6. 6.
    Andrade EL, Ferreira J, Andre E, Calixto JB (2006) Contractile mechanisms coupled to TRPA1 receptor activation in rat urinary bladder. Biochem Pharmacol 72:104–114PubMedGoogle Scholar
  7. 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–F1234Google Scholar
  8. 8.
    Andrade EL, Meotti FC, Calixto JB (2012) TRPA1 antagonists as potential analgesic drugs. Pharmacol Ther 133:189–204PubMedGoogle Scholar
  9. 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 158:1621–1628PubMedGoogle Scholar
  10. 10.
    Anke H, Sterner O (1991) Comparison of the antimicrobial and cytotoxic activities of twenty unsaturated sesquiterpene dialdehydes from plants and mushrooms. Planta Medica 57:344–346PubMedGoogle Scholar
  11. 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 232:90–99PubMedGoogle Scholar
  12. 12.
    Atoyan R, Shander D, Botchkareva NV (2009) Non-Neuronal Expression of Transient Receptor Potential Type A1 (TRPA1) in Human Skin. J Invest Dermatol 129:2312–2315PubMedGoogle Scholar
  13. 13.
    Aubdool AA, Brain SD (2011) Neurovascular aspects of skin neurogenic inflammation. J Investig Dermatol Symp Proc 15:33–39PubMedGoogle Scholar
  14. 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 41:849–857PubMedGoogle Scholar
  15. 15.
    Bang S, Hwang SW (2009) Polymodal Ligand Sensitivity of TRPA1 and Its Modes of Interactions. J Gen Physiol 133:257–262PubMedGoogle Scholar
  16. 16.
    Bang S, Kim KY, Yoo S, Kim YG, Hwang SW (2007) Transient receptor potential A1 mediates acetaldehyde-evoked pain sensation. Eur J Neurosci 26:2516–2523PubMedGoogle Scholar
  17. 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 161:707–720PubMedGoogle Scholar
  18. 18.
    Banke TG (2011) The dilated TRPA1 channel pore state is blocked by amiloride and analogues. Brain Res 1381:21–30PubMedGoogle Scholar
  19. 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–C1444Google Scholar
  20. 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 53:5085–5107PubMedGoogle Scholar
  21. 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 20:1690–1698PubMedGoogle Scholar
  22. 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 17:1636–1639PubMedGoogle Scholar
  23. 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 124:1269–1282PubMedGoogle Scholar
  24. 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 102:12248–12252PubMedGoogle Scholar
  25. 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 11:772–779PubMedGoogle Scholar
  26. 26.
    Belvisi MG, Dubuis E, Birrell MA (2011) Transient receptor potential A1 channels: insights into cough and airway inflammatory disease. Chest 140:1040–1047PubMedGoogle Scholar
  27. 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 1793:1279–1288PubMedGoogle Scholar
  28. 28.
    Bessac BF, Jordt S-E (2008) Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control. Physiology (Bethesda) 23:360–370Google Scholar
  29. 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 23:1102–1114PubMedGoogle Scholar
  30. 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 118:1899–1910PubMedGoogle Scholar
  31. 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 341:360–368PubMedGoogle Scholar
  32. 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:e17387PubMedGoogle Scholar
  33. 33.
    Bobkov YV, Corey EA, Ache BW (2011) The pore properties of human nociceptor channel TRPA1 evaluated in single channel recordings. Biochim Biophys Acta 1808:1120–1128PubMedGoogle Scholar
  34. 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 7:78PubMedGoogle Scholar
  35. 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 589:3575–3593PubMedGoogle Scholar
  36. 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 137:2084–2095PubMedGoogle Scholar
  37. 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 55:6236–6243PubMedGoogle Scholar
  38. 38.
    Brooks SM (2010) Occupational, environmental, and irritant-induced cough. Otolaryngol Clin North Am 43:85–96PubMedGoogle Scholar
  39. 39.
    Brooks SM, Bernstein IL (2011) Irritant-induced airway disorders. Immunol Allergy Clin North Am 31:747–768PubMedGoogle Scholar
  40. 40.
    Brownlee M (2011) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820Google Scholar
  41. 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 689:211–218PubMedGoogle Scholar
  42. 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–e445PubMedGoogle Scholar
  43. 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 56:1199–1220PubMedGoogle Scholar
  44. 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) 106:9099–9104Google Scholar
  45. 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:e38005PubMedGoogle Scholar
  46. 46.
    Caspani O, Heppenstall PA (2009) TRPA1 and Cold Transduction: An Unresolved Issue? J Gen Physiol 133:245–249PubMedGoogle Scholar
  47. 47.
    Caterina MJ (2007) Chemical biology: Sticky spices. Nature 445:491–492PubMedGoogle Scholar
  48. 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–G91PubMedGoogle Scholar
  49. 49.
    Cavanaugh EJ, Simkin D, Kim D (2008) Activation of TRPA1 by Mustard oil, Tetrahydrocannabinol and Ca2+ Reveals Different Functional States of TRPA1. Neuroscience 154:1467–1476PubMedGoogle Scholar
  50. 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 13:861–868PubMedGoogle Scholar
  51. 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 152:1165–1172PubMedGoogle Scholar
  52. 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 5:3PubMedGoogle Scholar
  53. 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 28:5063–5071PubMedGoogle Scholar
  54. 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 122:691–701PubMedGoogle Scholar
  55. 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 1383:36–42PubMedGoogle Scholar
  56. 56.
    Christianson JA, Bielefeldt K, Malin SA, Davis BM (2010) Neonatal colon insult alters growth factor expression and TRPA1 responses in adult mice. Pain 151:540–549PubMedGoogle Scholar
  57. 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 1284:54–67PubMedGoogle Scholar
  58. 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. 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–E1191PubMedGoogle Scholar
  60. 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 432:723–730PubMedGoogle Scholar
  61. 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 4:30PubMedGoogle Scholar
  62. 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 286:38168–38176PubMedGoogle Scholar
  63. 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 117:1978–1987Google Scholar
  64. 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 163:1479–1494Google Scholar
  65. 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 325:1007–1015PubMedGoogle Scholar
  66. 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 20:276–279PubMedGoogle Scholar
  67. 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 53:559–567PubMedGoogle Scholar
  68. 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 30:15165–15174PubMedGoogle Scholar
  69. 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 16:1299–1305PubMedGoogle Scholar
  70. 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 578:201–208PubMedGoogle Scholar
  71. 71.
    Diogenes A, Akopian AN, Hargreaves KM (2007) NGF up-regulates TRPA1: implications for orofacial pain. J Dent Res 86:550–555PubMedGoogle Scholar
  72. 72.
    Doerner JF, Gisselmann G, Hatt H, Wetzel CH (2007) Transient receptor potential channel A1 is directly gated by calcium ions. J Biol Chem 282:13180–13189PubMedGoogle Scholar
  73. 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 80:353–357Google Scholar
  74. 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 62:349–356PubMedGoogle Scholar
  75. 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 72:450–455PubMedGoogle Scholar
  76. 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 70:826–831PubMedGoogle Scholar
  77. 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 27:3151–3160PubMedGoogle Scholar
  78. 78.
    Dunham JP, Leith JL, Lumb BM, Donaldson LF (2010) Transient Receptor Potential Channel A1 and noxious cold responses in rat cutaneous nociceptors. Neuroscience 165:412–1419Google Scholar
  79. 79.
    Earley S (2012) TRPA1 Channels in the Vasculature. Br J Pharmacol 167:13–22PubMedGoogle Scholar
  80. 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–U166PubMedGoogle Scholar
  81. 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 287:28291–28306PubMedGoogle Scholar
  82. 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 153:1949–1958PubMedGoogle Scholar
  83. 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 37:473–478PubMedGoogle Scholar
  84. 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 152:2211–2223PubMedGoogle Scholar
  85. 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 1230:80–90PubMedGoogle Scholar
  86. 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 26:8578–8587PubMedGoogle Scholar
  87. 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 141:1346–1358PubMedGoogle Scholar
  88. 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 283:24136–24144PubMedGoogle Scholar
  89. 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 28:7863–7875PubMedGoogle Scholar
  90. 90.
    Fajardo O, Meseguer V, Belmonte C, Viana F (2008) TRPA1 channels: Novel targets of 1,4-dihydropyridines. Channels (Austin) 2:429–438Google Scholar
  91. 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 63:819–829PubMedGoogle Scholar
  92. 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 285:34781–34792PubMedGoogle Scholar
  93. 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 5:17PubMedGoogle Scholar
  94. 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 33:1385–1400PubMedGoogle Scholar
  95. 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 151:153–160PubMedGoogle Scholar
  96. 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 118:4049–4057PubMedGoogle Scholar
  97. 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 19:429–436Google Scholar
  98. 98.
    Garrison SL, Stucky CL (2011) The Dynamic TRPA1 Channel: A Suitable Pharmacological Pain Target? Curr Pharm Biotechnol 12:1689–1697PubMedGoogle Scholar
  99. 99.
    Garrity PA (2011) Weakly acidic, but strongly irritating: TRPA1 and the activation of nociceptors by cytoplasmic acidification. J Gen Physiol 137:489–491PubMedGoogle Scholar
  100. 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:a003962PubMedGoogle Scholar
  101. 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:e28644Google Scholar
  102. 102.
    Gentry C, Stoakley N, Andersson DA, Bevan S (2010) The roles of iPLA2, TRPM8 and TRPA1 in chemically induced cold hypersensitivity. Mol Pain 6:4PubMedGoogle Scholar
  103. 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 67:887–894PubMedGoogle Scholar
  104. 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 53:7011–7020PubMedGoogle Scholar
  105. 105.
    Grace MS, Belvisi MG (2010) TRPA1 receptors in Cough. Pulm Pharmacol Ther 24:286–288PubMedGoogle Scholar
  106. 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 67:891–900Google Scholar
  107. 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 464:1006–1012PubMedGoogle Scholar
  108. 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 57:902–910PubMedGoogle Scholar
  109. 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 109:6721–6726PubMedGoogle Scholar
  110. 110.
    Gu Q, Lin RL (2010) Heavy metals zinc, cadmium and copper stimulate pulmonary sensory neurons via direct activation of TRPA1. J Appl Physiol 108:891–897PubMedGoogle Scholar
  111. 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 56:1604–1609PubMedGoogle Scholar
  112. 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 454:217–220PubMedGoogle Scholar
  113. 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 pressGoogle Scholar
  114. 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 65:1631–1652PubMedGoogle Scholar
  115. 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 119:951–957Google Scholar
  116. 116.
    Hermanstyne TO, Markowitz K, Fan L, Gold MS (2008) Mechanotransducers in rat pulpal afferents. J Dent Res 87:834–838PubMedGoogle Scholar
  117. 117.
    Hill K, Schaefer M (2007) TRPA1 is differentially modulated by the amphiphatic molecules trinitrophenol and chlorpromazine. J Biol Chem 282:7145–7153PubMedGoogle Scholar
  118. 118.
    Hill K, Schaefer M (2008) Ultraviolet light and photosensitising agents activate TRPA1 via generation of oxidative stress. Cell Calcium 45:55–164Google Scholar
  119. 119.
    Hinman A, Chuang H-H, Bautista DM, Julius D (2007) TRP channel activation by reversible covalent modification. Proc Natl Acad Sci (USA) 103:19564–19568Google Scholar
  120. 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 27:2435–2443PubMedGoogle Scholar
  121. 121.
    Hu H, Bandell M, Petrus MJ, Zhu MX, Patapoutian A (2009) Zinc activates damage-sensing TRPA1 ion channels. Nat Chem Biol 5:183–190PubMedGoogle Scholar
  122. 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 459:579–592Google Scholar
  123. 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:e30090PubMedGoogle Scholar
  124. 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 210:403–415PubMedGoogle Scholar
  125. 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 90:47–54PubMedGoogle Scholar
  126. 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 85:60–69PubMedGoogle Scholar
  127. 127.
    Jain A, Bronneke S, Kolbe L, Stab F, Wenck H, Neufang G (2011) TRP-channel-specific cutaneous eicosanoid release patterns. Pain 152:2765–2772PubMedGoogle Scholar
  128. 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 274:7325–7333PubMedGoogle Scholar
  129. 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 427:260–265PubMedGoogle Scholar
  130. 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–G1143PubMedGoogle Scholar
  131. 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–G701PubMedGoogle Scholar
  132. 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 481:76–80Google Scholar
  133. 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–U155PubMedGoogle Scholar
  134. 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 27:9874–9884PubMedGoogle Scholar
  135. 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 457:77–89Google Scholar
  136. 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 98:773–783PubMedGoogle Scholar
  137. 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 106:1273–1278PubMedGoogle Scholar
  138. 138.
    Kerstein PC, Del Camino D, Moran MM, Stucky CL (2009) Pharmacological blockade of TRPA1 inhibits mechanical firing in nociceptors. Mol Pain 5:19PubMedGoogle Scholar
  139. 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 27:6500–6509PubMedGoogle Scholar
  140. 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–C99Google Scholar
  141. 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 38:1087–1092PubMedGoogle Scholar
  142. 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 107:8440–8445PubMedGoogle Scholar
  143. 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 518:687–698Google Scholar
  144. 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 19:390–400PubMedGoogle Scholar
  145. 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 10:568–577PubMedGoogle Scholar
  146. 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 105:1701–1710PubMedGoogle Scholar
  147. 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 21:554–564Google Scholar
  148. 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 30:12219–12229PubMedGoogle Scholar
  149. 149.
    Koivisto A (2012) Sustained TRPA1 activation in vivo. Acta Physiol 204:248–254Google Scholar
  150. 150.
    Kollarik M, Brozmanova M (2009) Cough and gastroesophageal reflux: Insights from animal models. Pulm Pharmacol Ther 22:130–134PubMedGoogle Scholar
  151. 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 463:549–559Google Scholar
  152. 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 58:1342–1352PubMedGoogle Scholar
  153. 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 26:1139–1147PubMedGoogle Scholar
  154. 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 341:205–212PubMedGoogle Scholar
  155. 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 27:4443–4451PubMedGoogle Scholar
  156. 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 66:671–680PubMedGoogle Scholar
  157. 157.
    Kunkler PE, Ballard CJ, Oxford GS, Hurley JH (2010) TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation. Pain 152:38–44PubMedGoogle Scholar
  158. 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 37:167–177PubMedGoogle Scholar
  159. 159.
    Kwan KY, Corey DP (2009) Burning Cold: Involvement of TRPA1 in Noxious Cold Sensation. J Gen Physiol 133:251–256PubMedGoogle Scholar
  160. 160.
    Kwan KY, Glazer JM, Corey DP, Rice FL, Stucky CL (2009) TRPA1 modulates mechanotransduction in cutaneous sensory neurons. J Neurosci 29:4808–4819PubMedGoogle Scholar
  161. 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 11:871–873Google Scholar
  162. 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 186:179–187PubMedGoogle Scholar
  163. 163.
    Latorre R (2009) Perspectives on TRP Channel Structure and the TRPA1 Puzzle. J Gen Physiol 133:227–229PubMedGoogle Scholar
  164. 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 503:157–162PubMedGoogle Scholar
  165. 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 153:1739–1749PubMedGoogle Scholar
  166. 166.
    Lefer DJ (2007) A new gaseous signaling molecule emerges: Cardioprotective role of hydrogen sulfide. Proc Natl Acad Sci U S A 104:17907–17908PubMedGoogle Scholar
  167. 167.
    Leffler A, Lattrell A, Kronewald S, Niedermirtl F, Nau C (2011) Activation of TRPA1 by membrane permeable local anesthetics. Mol Pain 7:62PubMedGoogle Scholar
  168. 168.
    Li L, Bhatia M, Moore PK (2006) Hydrogen sulphide–a novel mediator of inflammation? Curr Opin Pharmacol 6:125–129PubMedGoogle Scholar
  169. 169.
    Liang J, Bi H, Ji W (2010) Involvement of TRPA1 in ET-1-induced pain-like behavior in mice. Neuroreport 21:201–205PubMedGoogle Scholar
  170. 170.
    Liu T, Ji RR (2012) Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice. Neurosci Bull 28:145–154PubMedGoogle Scholar
  171. 171.
    Liu K, Samuel M, Ho M, Harrison RK, Paslay JW (2010) NPPB structure-specifically activates TRPA1 channels. Biochem Pharmacol 80:113–121PubMedGoogle Scholar
  172. 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 42:2–9PubMedGoogle Scholar
  173. 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 445:541–545PubMedGoogle Scholar
  174. 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 15:929–934PubMedGoogle Scholar
  175. 175.
    Macpherson LJ, Patapoutian A (2010) Channels: Flies feel your pain. Nat Chem Biol 6:252–253PubMedGoogle Scholar
  176. 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 27:11412–11415PubMedGoogle Scholar
  177. 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 73:1225–1234PubMedGoogle Scholar
  178. 178.
    Maher SA, Dubuis ED, Belvisi MG (2011) G-protein coupled receptors regulating cough. Curr Opin Pharmacol 11:248–253PubMedGoogle Scholar
  179. 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 162:584–596PubMedGoogle Scholar
  180. 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 26:8588–8599PubMedGoogle Scholar
  181. 181.
    Markowitz K (2009) Pretty painful: Why does tooth bleaching hurt? Med Hypotheses 74:835–840PubMedGoogle Scholar
  182. 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 73:1021–1027PubMedGoogle Scholar
  183. 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 463:561–569Google Scholar
  184. 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 105:12045–12050PubMedGoogle Scholar
  185. 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) 105:8784–8789Google Scholar
  186. 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 287:27087–27094PubMedGoogle Scholar
  187. 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 6:14PubMedGoogle Scholar
  188. 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 104:13525–13530PubMedGoogle Scholar
  189. 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 57:1982–1989PubMedGoogle Scholar
  190. 190.
    Michel MC (2007) Editorial Comment on: Distribution and Function of the Hydrogen Sulfide-Sensitive TRPA1 Ion Channel in Rat Urinary Bladder. Eur Urol 53:399–400PubMedGoogle Scholar
  191. 191.
    Miyamoto T, Dubin AE, Petrus MJ, Patapoutian A (2009) TRPV1 and TRPA1 mediate peripheral nitric oxide-induced nociception in mice. PLoS One 4:e7596PubMedGoogle Scholar
  192. 192.
    Miyamoto R, Otsuguro KI, Ito S (2011) Time- and concentration-dependent activation of TRPA1 by hydrogen sulfide in rat DRG neurons. Neurosci Lett 499:137–142PubMedGoogle Scholar
  193. 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 140:1337–1348PubMedGoogle Scholar
  194. 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 22:1674–1677PubMedGoogle Scholar
  195. 195.
    Motter AL, Ahern GP (2012) TRPA1 Is a Polyunsaturated Fatty Acid Sensor in Mammals. PLoS One 7:e38439PubMedGoogle Scholar
  196. 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 31:350–358PubMedGoogle Scholar
  197. 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 25:4052–4061PubMedGoogle Scholar
  198. 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 99:3609–3618PubMedGoogle Scholar
  199. 199.
    Nagatomo K, Kubo Y (2008) Caffeine activates mouse TRPA1 channels but suppresses human TRPA1 channels. Proc Natl Acad Sci U S A 105:17373–17378PubMedGoogle Scholar
  200. 200.
    Namer B, Seifert F, Handwerker HO, Maihofner C (2005) TRPA1 and TRPM8 activation in humans: effects of cinnamaldehyde and menthol. Neuroreport 16:955–959PubMedGoogle Scholar
  201. 201.
    Narukawa M, Koizumi K, Iwasaki Y, Kubota K, Watanabe T (2010) Galangal Pungent Component, 1′-Acetoxychavicol Acetate, Activates TRPA1. Biosci Biotechnol Biochem 74:1694–1696PubMedGoogle Scholar
  202. 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 586:1595–1604PubMedGoogle Scholar
  203. 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 152:1621–1631PubMedGoogle Scholar
  204. 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 24:4904–4916PubMedGoogle Scholar
  205. 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 135:376–390PubMedGoogle Scholar
  206. 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:e24343PubMedGoogle Scholar
  207. 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 85:145–157PubMedGoogle Scholar
  208. 208.
    Nilius B, Owsianik G (2011) The transient receptor potential family of ion channels. Genome Biol 12:218–229PubMedGoogle Scholar
  209. 209.
    Nilius B, Owsianik G, Voets T (2008) Transient receptor potential channels meet phosphoinositides. EMBO J 27:2809–2816PubMedGoogle Scholar
  210. 210.
    Nilius B, Owsianik G, Voets T, Peters JA (2007) Transient Receptor Potential Channels in Disease. Physiol Rev 87:165–217PubMedGoogle Scholar
  211. 211.
    Nilius B, Prenen J, Owsianik G (2011) Irritating Channels: the case of TRPA1. J Physiol 589:1543–1549PubMedGoogle Scholar
  212. 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 106:3408–3413PubMedGoogle Scholar
  213. 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 35:346–354PubMedGoogle Scholar
  214. 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 218:335–343PubMedGoogle Scholar
  215. 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 166:1738–1743PubMedGoogle Scholar
  216. 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 74:1068–1072PubMedGoogle Scholar
  217. 217.
    Panzano VC, Kang K, Garrity PA (2010) Infrared Snake Eyes: TRPA1 and the Thermal Sensitivity of the Snake Pit Organ. Sci Signal 3:pe22PubMedGoogle Scholar
  218. 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 509:171–177PubMedGoogle Scholar
  219. 219.
    Patapoutian A, Peier AM, Story GM, Viswanath V (2003) ThermoTRP channels and beyond: mechanisms of temperature sensation. Nat Rev Neurosci 4:529–539PubMedGoogle Scholar
  220. 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 89:945–954PubMedGoogle Scholar
  221. 221.
    Patil MJ, Jeske NA, Akopian AN (2010) TRPV1 regulates activation and modulation of TRPA1 by Ca2+. Neuroscience 171:1109–1119PubMedGoogle Scholar
  222. 222.
    Patil M, Patwardhan A, Salas MM, Hargreaves KM, Akopian AN (2011) Cannabinoid receptor antagonists AM251 and AM630 activate TRPA1 in sensory neurons. Neuropharmacology 61:778–788PubMedGoogle Scholar
  223. 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 36:234–241PubMedGoogle Scholar
  224. 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 666:1–4PubMedGoogle Scholar
  225. 225.
    Peterlin Z, Chesler A, Firestein S (2007) A painful Trp can be a bonding experience. Neuron 53:635–638PubMedGoogle Scholar
  226. 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 31:999–1009PubMedGoogle Scholar
  227. 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 379:980–984PubMedGoogle Scholar
  228. 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 74:2019–2022PubMedGoogle Scholar
  229. 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–U656PubMedGoogle Scholar
  230. 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 87:760–768PubMedGoogle Scholar
  231. 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 689:56–64PubMedGoogle Scholar
  232. 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 28:10102–10110PubMedGoogle Scholar
  233. 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 pressGoogle Scholar
  234. 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 67:19–25PubMedGoogle Scholar
  235. 235.
    Rawls SM, Benamar K (2011) Effects of opioids, cannabinoids, and vanilloids on body temperature. Front Biosci (Schol Ed) 3:822–845Google Scholar
  236. 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 2:843–858Google Scholar
  237. 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 157:1398–1409Google Scholar
  238. 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 139:519–526PubMedGoogle Scholar
  239. 239.
    Rubin BK (2007) Mucolytics, expectorants, and mucokinetic medications. Respir Care 52:859–865PubMedGoogle Scholar
  240. 240.
    Ruparel NB, Patwardhan AM, Akopian AN, Hargreaves KM (2011) Desensitization of TRPA1 by the TRPV1-selective cannabinoid arachidonoly-2chloroethanolamine (ACEA). Mol Pharmacol 80:117–123PubMedGoogle Scholar
  241. 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 63:30–36PubMedGoogle Scholar
  242. 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 287:30743–30754PubMedGoogle Scholar
  243. 243.
    Salas MM, Hargreaves KM, Akopian AN (2009) TRPA1-mediated responses in trigeminal sensory neurons: interaction between TRPA1 and TRPV1. Europ J Neurosci 29:1568–1578Google Scholar
  244. 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 433:197–204PubMedGoogle Scholar
  245. 245.
    Saunders CJ, Silver WL (2008) The Respiratory Response of TRPV1 Knockout Mice to Trigeminal Irritants. Chem Senses 33:S104–S104Google Scholar
  246. 246.
    Sawada Y, Hosokawa H, Hori A, Matsumura K, Kobayashi S (2007) Cold sensitivity of recombinant TRPA1 channels. Brain Res 1160:39–46PubMedGoogle Scholar
  247. 247.
    Sawada Y, Hosokawa H, Matsumura K, Kobayashi S (2008) Activation of transient receptor potential ankyrin 1 by hydrogen peroxide. Eur J Neurosci 27:1131–1142PubMedGoogle Scholar
  248. 248.
    Schmidt M, Dubin AE, Petrus MJ, Earley TJ, Patapoutian A (2009) Nociceptive Signals Induce Trafficking of TRPA1 to the Plasma Membrane. Neuron 64:498–509PubMedGoogle Scholar
  249. 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 140:140Google Scholar
  250. 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 333:883–895PubMedGoogle Scholar
  251. 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, piiPubMedGoogle Scholar
  252. 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 15:70–80Google Scholar
  253. 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 165:1476–1486PubMedGoogle Scholar
  254. 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 88:1077–1087PubMedGoogle Scholar
  255. 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 32:6364–6372PubMedGoogle Scholar
  256. 256.
    Smith MP, Beacham D, Ensor E, Koltzenburg M (2004) Cold-sensitive, menthol-insensitive neurons in the murine sympathetic nervous system. Neuroreport 15:1399–1403PubMedGoogle Scholar
  257. 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 85:15167–15177Google Scholar
  258. 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 12:729–740Google Scholar
  259. 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 18:1584–1594PubMedGoogle Scholar
  260. 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 112:819–829PubMedGoogle Scholar
  261. 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 53:391–399PubMedGoogle Scholar
  262. 262.
    Sun B, Bang SI, Jin YH (2009) Transient receptor potential A1 increase glutamate release on brain stem neurons. Neuroreport 20:1002–1006PubMedGoogle Scholar
  263. 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–H2438PubMedGoogle Scholar
  264. 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 106:13606–13611Google Scholar
  265. 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 287:18067–18077PubMedGoogle Scholar
  266. 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 23:3179–3192PubMedGoogle Scholar
  267. 267.
    Szabo C (2007) Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 6:917–935PubMedGoogle Scholar
  268. 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. 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 28:701–711Google Scholar
  270. 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) 2:287–298Google Scholar
  271. 271.
    Takahashi N, Mori Y (2011) TRP Channels as Sensors and Signal Integrators of Redox Status Changes. Front Pharmacol 2:58PubMedGoogle Scholar
  272. 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 129:1050–1060Google Scholar
  273. 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 12:1293–1299Google Scholar
  274. 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 75:820–829PubMedGoogle Scholar
  275. 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 40:756–762PubMedGoogle Scholar
  276. 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) 586:3447–3459Google Scholar
  277. 277.
    Taylor-Clark TE, Nassenstein C, McAlexander MA, Undem BJ (2008) TRPA1: A potential target for anti-tussive therapy. Pulm Pharmacol Ther 22:71–74PubMedGoogle Scholar
  278. 278.
    Taylor-Clark TE, Undem BJ (2010) Ozone activates airway nerves via the selective stimulation of TRPA1 ion channels. J Physiol (Lond) 588:423–433Google Scholar
  279. 279.
    Taylor-Clark TE, Undem BJ (2011) Sensing pulmonary oxidative stress by lung vagal afferents. Respir Physiol Neurobiol 178:406–413PubMedGoogle Scholar
  280. 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 73:274–281PubMedGoogle Scholar
  281. 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 104:13519–13524PubMedGoogle Scholar
  282. 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 pressGoogle Scholar
  283. 283.
    Undem BJ, Carr MJ (2010) Targeting primary afferent nerves for novel antitussive therapy. Chest 137:177–184PubMedGoogle Scholar
  284. 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 31:1960–1973PubMedGoogle Scholar
  285. 285.
    Vilceanu D, Stucky CL (2010) TRPA1 Mediates Mechanical Currents in the Plasma Membrane of Mouse Sensory Neurons. PLoS One 5:e12177PubMedGoogle Scholar
  286. 286.
    Vriens J, Appendino G, Nilius B (2009) Pharmacology of vanilloid transient receptor potential cation channels Trpv. Mol Pharmacol 75:1262–1279PubMedGoogle Scholar
  287. 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 137:493–505PubMedGoogle Scholar
  288. 288.
    Wang YY, Chang RB, Liman ER (2010) TRPA1 Is a Component of the Nociceptive Response to CO2. J Neurosci 30:12958–12963PubMedGoogle Scholar
  289. 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 283:32691–32703PubMedGoogle Scholar
  290. 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 287:6169–6176PubMedGoogle Scholar
  291. 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 131:1241–1251PubMedGoogle Scholar
  292. 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:e25890PubMedGoogle Scholar
  293. 293.
    Wang S, Lee J, Ro JY, Chung MK (2012) Warmth suppresses and desensitizes damage-sensing ion channel TRPA1. Mol Pain 8:22PubMedGoogle Scholar
  294. 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 30:967–974PubMedGoogle Scholar
  295. 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 4:442–449PubMedGoogle Scholar
  296. 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 111:147–154PubMedGoogle Scholar
  297. 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 117:137–148PubMedGoogle Scholar
  298. 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 152:582–591PubMedGoogle Scholar
  299. 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 45:391–400PubMedGoogle Scholar
  300. 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 pressGoogle Scholar
  301. 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 152:709–716PubMedGoogle Scholar
  302. 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 14:595–602Google Scholar
  303. 303.
    Wood H (2010) Pain: new familial pain syndrome caused by TRPA1 mutation. Nat Rev Neurol 6:412PubMedGoogle Scholar
  304. 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 62:381–404PubMedGoogle Scholar
  305. 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 28:9640–9651PubMedGoogle Scholar
  306. 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 9:628–635Google Scholar
  307. 307.
    Xu J, Sornborger AT, Lee JK, Shen P (2008) Drosophila TRPA channel modulates sugar-stimulated neural excitation, avoidance and social response. Nat Neurosci 11:676–682PubMedGoogle Scholar
  308. 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 440:237–241PubMedGoogle Scholar
  309. 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 66:99–105PubMedGoogle Scholar
  310. 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 10:1667–1676PubMedGoogle Scholar
  311. 311.
    Yokoyama S, Altun A, Denardo DF (2011) Molecular Convergence of Infrared Vision in Snakes. Mol Biol Evol 28:45–48PubMedGoogle Scholar
  312. 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 655:31–37PubMedGoogle Scholar
  313. 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 7:41PubMedGoogle Scholar
  314. 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–G42PubMedGoogle Scholar
  315. 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–G265PubMedGoogle Scholar
  316. 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 35:797–803PubMedGoogle Scholar
  317. 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 97:966–978PubMedGoogle Scholar
  318. 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 pressGoogle Scholar
  319. 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 27:605–611PubMedGoogle Scholar
  320. 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 114:1169–1179PubMedGoogle Scholar
  321. 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 1:43–55PubMedGoogle Scholar
  322. 322.
    Zhong J, Minassi A, Prenen J, Taglialatela-Scafati O, Appendino G, Nilius B (2011) Umbellulone modulates TRP channels. Pflügers Arch Eur J Physiol 462:861–870Google Scholar
  323. 323.
    Zhong J, Pollastro F, Prenen J, Zhu Z, Appendino G, Nilius B (2011) Ligustilide: a novel TRPA1 modulator. Pflugers Arch Eur J Physiol 462:841–849Google Scholar
  324. 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 177:327–332PubMedGoogle Scholar
  325. 325.
    Zurborg S, Yurgionas B, Jira JA, Caspani O, Heppenstall PA (2007) Direct activation of the ion channel TRPA1 by Ca(2+). Nat Neorsci 10:277–279Google Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Bernd Nilius
    • 1
  • Giovanni Appendino
    • 2
  • Grzegorz Owsianik
    • 1
  1. 1.Department of Cellular and Molecular Medicine, Laboratory Ion Channel ResearchKU LeuvenLeuvenBelgium
  2. 2.Dipartimento di Scienze Chimiche AlimentariFarmaceutiche e FarmacologicheNovaraItaly

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