Short isoforms of the cold receptor TRPM8 inhibit channel gating by mimicking heat action rather than chemical inhibitors

José A. Fernández, Roman Skryma, Gabriel Bidaux, Karl L. Magleby, C. Norman Scholfield, J. Graham McGeown, Natalia Prevarskaya, Alexander V. Zholos

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Transient receptor potential (TRP) channels couple various environmental factors to changes in membrane potential, calcium influx, and cell signaling. They also integrate multiple stimuli through their typically polymodal activation. Thus, although the TRPM8 channel has been extensively investigated as the major neuronal cold sensor, it is also regulated by various chemicals, as well as by several short channel isoforms. Mechanistic understanding of such complex regulation is facilitated by quantitative single-channel analysis. We have recently proposed a single-channel mechanism of TRPM8 regulation by voltage and temperature. Using this gating mechanism, we now investigate TRPM8 inhibition in cell-attached patches using HEK293 cells expressing TRPM8 alone or coexpressed with its short sM8-6 isoform. This is compared with inhibition by the chemicals N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1- carboxamide (BCTC) and clotrimazole or by elevated temperature.Wefound that within the seven-state single-channel gating mechanism, inhibition of TRPM8 by short sM8-6 isoforms closely resembles inhibition by increased temperature. In contrast, inhibition by BCTC and that by clotrimazole share a different set of common features.

Original languageEnglish (US)
Pages (from-to)2963-2970
Number of pages8
JournalJournal of Biological Chemistry
Volume287
Issue number5
DOIs
StatePublished - Jan 27 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Fernández, J. A., Skryma, R., Bidaux, G., Magleby, K. L., Scholfield, C. N., McGeown, J. G., Prevarskaya, N., & Zholos, A. V. (2012). Short isoforms of the cold receptor TRPM8 inhibit channel gating by mimicking heat action rather than chemical inhibitors. Journal of Biological Chemistry, 287(5), 2963-2970. https://doi.org/10.1074/jbc.M111.272823