Pflügers Archiv - European Journal of Physiology

, Volume 459, Issue 4, pp 579–592

Activation of TRPA1 channels by fenamate nonsteroidal anti-inflammatory drugs

  • Hongzhen Hu
  • Jinbin Tian
  • Yingmin Zhu
  • Chunbo Wang
  • Rui Xiao
  • Jeffrey M. Herz
  • Jackie D. Wood
  • Michael X. Zhu
Ion Channels, Receptors and Transporters

Abstract

Transient receptor potential A1 (TRPA1) forms nonselective cation channels implicated in acute inflammatory pain and nociception. The mechanism of ligand activation of TRPA1 may involve either covalent modification of cysteine residues or conventional reversible ligand–receptor interactions. For certain electrophilic prostaglandins, covalent modification has been considered as the main mechanism involved in their stimulatory effect on TRPA1. Because some nonsteroidal anti-inflammatory drugs (NSAIDs) are structural analogs of prostaglandins, we examined several nonelectrophilic NSAIDs on TRPA1 activation using electrophysiological techniques and intracellular Ca2+ measurements and found that a selected group of NSAIDs can act as TRPA1 agonists. Extracellularly applied flufenamic, niflumic, and mefenamic acid, as well as flurbiprofen, ketoprofen, diclofenac, and indomethacin, rapidly activated rat TRPA1 expressed in Xenopus oocytes and human TRPA1 endogenously expressed in WI-38 fibroblasts. Similarly, the NSAID ligands activated human TRPA1 inducibly expressed in HEK293 cells, but the responses were absent in uninduced and parental HEK293 cells. The response to fenamate agonists was blocked by TRPA1 antagonists, AP-18, HC-030031, and ruthenium red. At subsaturating concentrations, the fenamate NSAIDs also potentiate the activation of TRPA1 by allyl isothiocyanate, cinnamaldehyde, and cold, demonstrating positive synergistic interactions with other well-characterized TRPA1 activators. Importantly, among several thermosensitive TRP channels, the stimulatory effect is specific to TRPA1 because flufenamic acid inhibited TRPV1, TRPV3, and TRPM8. We conclude that fenamate NSAIDs are a novel class of potent and reversible direct agonists of TRPA1. This selective group of TRPA1-stimulating NSAIDs should provide a structural basis for developing novel ligands that noncovalently interact with TRPA1 channels.

Keywords

NSAID TRP channel Pain Cancer Sensory neurons 

Abbreviations

2APB

2-Aminoethoxydiphenyl borate

AITC

Allyl isothiocyanate

CA

Cinnamaldehyde

[Ca2+]i

Intracellular Ca2+ concentration

COX

Cyclooxygenase

ECS

Extracellular solution

FFA

Flufenamic acid

MFA

Mefenamic acid

NFA

Niflumic acid

NSAIDs

Nonsteroidal anti-inflammatory drugs

TRP

Transient receptor potential

References

  1. 1.
    Albert AP, Pucovsky V, Prestwich SA, Large WA (2006) TRPC3 properties of a native constitutively active Ca2+-permeable cation channel in rabbit ear artery myocytes. J Physiol 571:361–369CrossRefPubMedGoogle Scholar
  2. 2.
    Andrè E, Campi B, Materazzi S, Trevisani M, Amadesi S, Massi D, Creminon C, Vaksman N, Nassini R, Civelli M, Baraldi PG, Poole DP, Bunnett NW, Geppetti P, Patacchini R (2008) Cigarette smoke-induced neurogenic inflammation is mediated by alpha, beta-unsaturated aldehydes and the TRPA1 receptor in rodents. J Clin Invest 118:2574–2582PubMedGoogle Scholar
  3. 3.
    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 41:849–857CrossRefPubMedGoogle Scholar
  4. 4.
    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 124:1269–1282CrossRefPubMedGoogle Scholar
  5. 5.
    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 102:12248–12252CrossRefPubMedGoogle Scholar
  6. 6.
    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 28:5063–5071CrossRefPubMedGoogle Scholar
  7. 7.
    Chung MK, Lee H, Mizuno A, Suzuki M, Caterina MJ (2004) 2-Aminoethoxydiphenyl borate activates and sensitizes the heat-gated ion channel TRPV3. J Neurosci 24:5177–5182CrossRefPubMedGoogle Scholar
  8. 8.
    Doerner JF, Gisselmann G, Hatt H, Wetzel CH (2007) Transient receptor potential channel A1 is directly gated by calcium ions. J Biol Chem 282:13180–13189CrossRefPubMedGoogle Scholar
  9. 9.
    Fajardo O, Meseguer V, Belmonte C, Viana F (2008) TRPA1 channels: novel targets of 1,4-dihydropyridines. Channels (Austin) 2:429–438Google Scholar
  10. 10.
    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 28:7863–7875CrossRefPubMedGoogle Scholar
  11. 11.
    Hill K, Benham CD, McNulty S, Randall AD (2004) Flufenamic acid is a H-dependent antagonist of TRPM2 channels. Neuropharmacology 47:450–460CrossRefPubMedGoogle Scholar
  12. 12.
    Hinman A, Chuang HH, Bautista DM, Julius D (2006) TRP channel activation by reversible covalent modification. Proc Natl Acad Sci U S A 103:19564–19568CrossRefPubMedGoogle Scholar
  13. 13.
    Hu H, Bandell M, Petrus MJ, Zhu MX, Patapoutian A (2009) Zinc activates damage-sensing TRPA1 ion channels. Nat Chem Biol 5:183–190CrossRefPubMedGoogle Scholar
  14. 14.
    Hu HZ, Gu Q, Wang C, Colton CK, Tang J, Kinoshita-Kawada M, Lee LY, Wood JD, Zhu MX (2004) 2-Aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. J Biol Chem 279:35741–35748CrossRefPubMedGoogle Scholar
  15. 15.
    Hu HZ, Xiao R, Wang C, Gao N, Colton CK, Wood JD, Zhu MX (2006) Potentiation of TRPV3 channel function by unsaturated fatty acids. J Cell Physiol 208:201–212CrossRefPubMedGoogle Scholar
  16. 16.
    Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim D, Oh U (2000) Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci U S A 97:6155–6160CrossRefPubMedGoogle Scholar
  17. 17.
    Inoue R, Okada T, Onoue H, Hara Y, Shimizu S, Naitoh S, Ito Y, Mori Y (2001) The transient receptor potential protein homologue TRP6 is the essential component of vascular α1-adrenoceptor-activated Ca2+-permeable cation channel. Circ Res 88:325–332PubMedGoogle Scholar
  18. 18.
    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 274:7325–7333CrossRefPubMedGoogle Scholar
  19. 19.
    Jentsch TJ, Stein V, Weinreich F, Zdebik AA (2002) Molecular structure and physiological function of chloride channels. Physiol Rev 82:503–568PubMedGoogle Scholar
  20. 20.
    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 427:260–265CrossRefPubMedGoogle Scholar
  21. 21.
    Jung S, Strotmann R, Schultz G, Plant TD (2002) TRPC6 is a candidate channel involved in receptor-stimulated cation currents in A7r5 smooth muscle cells. Am J Physiol Cell Physiol 282:C347–C359PubMedGoogle Scholar
  22. 22.
    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 27:9874–9884CrossRefPubMedGoogle Scholar
  23. 23.
    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 106:1273–1278CrossRefPubMedGoogle Scholar
  24. 24.
    Koh SD, Jun JY, Kim TW, Sanders KM (2002) A Ca2+-inhibited nonselective cation conductance contributes to pacemaker currents in mouse interstitial cell of Cajal. J Physiol 540:803–814CrossRefPubMedGoogle Scholar
  25. 25.
    Koizumi K, Iwasaki Y, Narukawa M, Iitsuka Y, Fukao T, Seki T, Ariga T, Watanabe T (2009) Diallyl sulfides in garlic activate both TRPA1 and TRPV1. Biochem Biophys Res Commun 382:545–548CrossRefPubMedGoogle Scholar
  26. 26.
    Kwan KY, Allchorne AJ, Vollrath MA, Christensen AP, Zhang DS, Woolf CJ, Corey DP (2006) TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 50:277–289CrossRefPubMedGoogle Scholar
  27. 27.
    Lee YM, Kim BJ, Kim HJ, Yang DK, Zhu MH, Lee KP, So I, Kim KW (2003) TRPC5 as a candidate for the nonselective cation channel activated by muscarinic stimulation in murine stomach. Am J Physiol Gastrointest Liver Physiol 284:G604–G616PubMedGoogle Scholar
  28. 28.
    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 445:541–545CrossRefPubMedGoogle Scholar
  29. 29.
    Macpherson LJ, Geierstanger BH, Viswanath V, Bandell M, Eid SR, Hwang S, Patapoutian A (2005) The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr Biol 15:929–934CrossRefPubMedGoogle Scholar
  30. 30.
    Maher M, Ao H, Banke T, Nasser N, Wu NT, Breitenbucher JG, Chaplan SR, Wickenden AD (2008) Activation of TRPA1 by farnesyl thiosalicylic acid. Mol Pharmacol 73:1225–1234CrossRefPubMedGoogle Scholar
  31. 31.
    Materazzi S, Nassini R, Andrè 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 105:12045–12050CrossRefPubMedGoogle Scholar
  32. 32.
    McIntyre P, McLatchie LM, Chambers A, Phillips E, Clarke M, Savidge J, Toms C, Peacock M, Shah K, Winter J, Weerasakera N, Webb M, Rang HP, Bevan S, James IF (2001) Pharmacological differences between the human and rat vanilloid receptor 1 (VR1). Br J Pharmacol 132:1084–1094CrossRefPubMedGoogle Scholar
  33. 33.
    Meseguer V, Karashima Y, Talavera K, D’Hoedt D, Donovan-Rodríguez T, Viana F, Nilius B, Voets T (2008) Transient receptor potential channels in sensory neurons are targets of the antimycotic agent clotrimazole. J Neurosci 28:576–586CrossRefPubMedGoogle Scholar
  34. 34.
    Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR (1993) Selectivity of nonsteroidal anti inflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A 90:11693–11697CrossRefPubMedGoogle Scholar
  35. 35.
    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 25:4052–4061CrossRefPubMedGoogle Scholar
  36. 36.
    Niforatos W, Zhang XF, Lake MR, Walter KA, Neelands T, Holzman TF, Scott VE, Faltynek CR, Moreland RB, Chen J (2007) Activation of TRPA1 channels by the fatty acid amide hydrolase inhibitor 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597). Mol Pharmacol 71:1209–1216CrossRefPubMedGoogle Scholar
  37. 37.
    Obata K, Katsura H, Mizushima T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Tokunaga A, Tominaga M, Noguchi K (2005) TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J Clin Invest 115:2393–2401CrossRefPubMedGoogle Scholar
  38. 38.
    Otsuguro K, Tang J, Tang Y, Xiao R, Freichel M, Tsvilovskyy V, Ito S, Flockerzi V, Zhu MX, Zholos AV (2008) Isoform-specific inhibition of TRPC4 channel by phosphatidylinositol 4,5-bisphosphate. J Biol Chem 283:10026–10036CrossRefPubMedGoogle Scholar
  39. 39.
    Ouellet M, Falgueyret JP, Percival MD (2004) Detergents profoundly affect inhibitor potencies against both cyclo-oxygenase isoforms. Biochem J 377:675–684CrossRefPubMedGoogle Scholar
  40. 40.
    Riendeau D, Charleson S, Cromlish W, Mancini JA, Wong E, Guay J (1997) Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol 75:1088–1095CrossRefPubMedGoogle Scholar
  41. 41.
    Sawada Y, Hosokawa H, Hori A, Matsumura K, Kobayashi S (2007) Cold sensitivity of recombinant TRPA1 channels. Brain Res 1160:39–46CrossRefPubMedGoogle Scholar
  42. 42.
    Schenker T, Trueb B (1998) Down-regulated proteins of mesenchymal tumor cells. Exp Cell Res 239:161–168CrossRefPubMedGoogle Scholar
  43. 43.
    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 112:819–829CrossRefPubMedGoogle Scholar
  44. 44.
    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
  45. 45.
    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 73:274–281CrossRefPubMedGoogle Scholar
  46. 46.
    Walker RL, Koh SD, Sergeant GP, Sanders KM, Horowitz B (2002) TRPC4 currents have properties similar to the pacemaker current in interstitial cells of Cajal. Am J Physiol Cell Physiol 283:C1637–C1645PubMedGoogle Scholar
  47. 47.
    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 283:32691–32703CrossRefPubMedGoogle Scholar
  48. 48.
    Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nilius B (2003) Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424:434–438CrossRefPubMedGoogle Scholar
  49. 49.
    White MM, Aylwin M (1999) Niflumic and flufenamic acids are potent reversible blockers of Ca2+-activated Cl channels in Xenopus oocytes. Mol Pharmacol 37:720–724Google Scholar
  50. 50.
    Zurborg S, Yurgionas B, Jira JA, Caspani O, Heppenstall PA (2007) Direct activation of the ion channel TRPA1 by Ca2+. Nat Neurosci 10:277–279CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Hongzhen Hu
    • 1
    • 5
  • Jinbin Tian
    • 2
  • Yingmin Zhu
    • 2
  • Chunbo Wang
    • 2
    • 6
  • Rui Xiao
    • 2
    • 7
  • Jeffrey M. Herz
    • 3
  • Jackie D. Wood
    • 1
  • Michael X. Zhu
    • 2
    • 4
    • 8
  1. 1.Department of Physiology and Cell BiologyThe Ohio State UniversityColumbusUSA
  2. 2.Department of Neuroscience and Center for Molecular NeurobiologyThe Ohio State UniversityColumbusUSA
  3. 3.Algomedix Inc.Mill CreekUSA
  4. 4.Department of BiochemistryThe Ohio State UniversityColumbusUSA
  5. 5.Genomics Institute of the Novartis Research FoundationSan DiegoUSA
  6. 6.Department of Cell and Developmental BiologyUniversity of North CarolinaChapel HillUSA
  7. 7.Life Sciences InstituteUniversity of MichiganAnn ArborUSA
  8. 8.Center for Molecular NeurobiologyThe Ohio State UniversityColumbusUSA

Personalised recommendations