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


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.


NSAID TRP channel Pain Cancer Sensory neurons 



2-Aminoethoxydiphenyl borate


Allyl isothiocyanate




Intracellular Ca2+ concentration




Extracellular solution


Flufenamic acid


Mefenamic acid


Niflumic acid


Nonsteroidal anti-inflammatory drugs


Transient receptor potential


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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

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