Pflügers Archiv - European Journal of Physiology

, Volume 459, Issue 4, pp 579–592

Activation of TRPA1 channels by fenamate nonsteroidal anti-inflammatory drugs

Authors

  • Hongzhen Hu
    • Department of Physiology and Cell BiologyThe Ohio State University
    • Genomics Institute of the Novartis Research Foundation
  • Jinbin Tian
    • Department of Neuroscience and Center for Molecular NeurobiologyThe Ohio State University
  • Yingmin Zhu
    • Department of Neuroscience and Center for Molecular NeurobiologyThe Ohio State University
  • Chunbo Wang
    • Department of Neuroscience and Center for Molecular NeurobiologyThe Ohio State University
    • Department of Cell and Developmental BiologyUniversity of North Carolina
  • Rui Xiao
    • Department of Neuroscience and Center for Molecular NeurobiologyThe Ohio State University
    • Life Sciences InstituteUniversity of Michigan
  • Jeffrey M. Herz
    • Algomedix Inc.
  • Jackie D. Wood
    • Department of Physiology and Cell BiologyThe Ohio State University
    • Department of Neuroscience and Center for Molecular NeurobiologyThe Ohio State University
    • Department of BiochemistryThe Ohio State University
    • Center for Molecular NeurobiologyThe Ohio State University
Ion Channels, Receptors and Transporters

DOI: 10.1007/s00424-009-0749-9

Cite this article as:
Hu, H., Tian, J., Zhu, Y. et al. Pflugers Arch - Eur J Physiol (2010) 459: 579. doi:10.1007/s00424-009-0749-9

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

NSAIDTRP channelPainCancerSensory 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

Copyright information

© Springer-Verlag 2009