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Pinacidil, a Katp channel opener, identified as a novel agonist for TRPA1

Chinese Science Bulletin volume 57, pages 1810–1817 (2012)Cite this article

Abstract

The transient receptor potential Ankyrin 1 (TRPA1) cation channel is activated by various pungent and irritant compounds, and it also mediates the perception of noxious cold. Identification of different agonists for this channel is important for understanding its activation mechanism. Therefore, a screen for novel TRPA1 agonists was performed using an agonist-induced calcium influx assay. Out of 90 compounds screened, pinacidil was identified as a novel agonist for this channel. Pinacidil is a known opener of the Katp channel, for which it has an EC50 value of 1–3 μmol/L. In comparison, the EC50 value of pinacidil for TRPA1 is relatively high (260 μmol/L). Recombinant HEK-TRPA1 cells did not respond to P1075, another Katp channel opener, suggesting that the effect of pinacidil on TRPA1 was highly specific. Further studies revealed that the agonist activity of pinacidil could be blocked by the TRP channel inhibitors, ruthenium red and HC-030031. Using glutathione (GSH) and site-specific mutagenesis, we demonstrated that pinacidil could activate TRPA1 by covalent modification of the critical amino acids C619, C639 and C663 in the N-terminus of TRPA1.

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Authors and Affiliations

  1. Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100029, China

    LiangHui Ma, YanQiu Bai & ShiYou Li

  2. Graduate University of Chinese Academy of Sciences, Beijing, 100049, China

    LiangHui Ma & YanQiu Bai

  3. Shanghai Jiao Tong University, Shanghai, 200240, China

    Jing Cao

  4. Sino-France Laboratory for Drug Screening, Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China

    Ying Deng, Bi Zhang & JianFeng Liu

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  1. LiangHui Ma
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Correspondence to JianFeng Liu.

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Ma, L., Deng, Y., Zhang, B. et al. Pinacidil, a Katp channel opener, identified as a novel agonist for TRPA1. Chin. Sci. Bull. 57, 1810–1817 (2012). https://doi.org/10.1007/s11434-012-5035-0

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  • DOI: https://doi.org/10.1007/s11434-012-5035-0

Keywords

  • TRPA1
  • pinacidil
  • covalent modification