The TRPM8 protein is a testosterone receptor: II. Functional evidence for an ionotropic effect of testosterone on TRPM8

Swapna Asuthkar, Lusine Demirkhanyan, Xiaohui Sun, Pia A. Elustondo, Vivek Krishnan, Padmamalini Baskaran, Kiran Kumar Velpula, Baskaran Thyagarajan, Evgeny V. Pavlov, Eleonora Zakharian

Research output: Contribution to journalArticle

Abstract

Testosterone is a key steroid hormone in the development of male reproductive tissues and the regulation of the central nervous system. The rapid signaling mechanism induced by testosterone affects numerous behavioral traits, including sexual drive, aggressiveness, and fear conditioning. However, the currently identified testosterone receptor(s) is not believed to underlie the fast signaling, suggesting an orphan pathway. Here we report that an ion channel from the transient receptor potential family, TRPM8, commonly known as the cold and menthol receptor is the major component of testosterone-induced rapid actions. Using cultured and primary cell lines along with the purified TRPM8 protein, we demonstrate that testosterone directly activates TRPM8 channel at low picomolar range. Specifically, testosterone induced TRPM8 responses in primary human prostate cells, PC3 prostate cancer cells, dorsal root ganglion neurons, and hippocampal neurons. Picomolar concentrations of testosterone resulted in full openings of the purified TRPM8 channel in planar lipid bilayers. Furthermore, acute applications of testosterone on human skin elicited a cooling sensation. Our data conclusively demonstrate that testosterone is an endogenous and highly potent agonist of TRPM8, suggesting a role of TRPM8 channels well beyond their well established function in somatosensory neurons. This discovery may further imply TRPM8 channel function in testosterone-dependent behavioral traits.

Original languageEnglish (US)
Pages (from-to)2670-2688
Number of pages19
JournalJournal of Biological Chemistry
Volume290
Issue number5
DOIs
StatePublished - Jan 30 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Asuthkar, S., Demirkhanyan, L., Sun, X., Elustondo, P. A., Krishnan, V., Baskaran, P., Velpula, K. K., Thyagarajan, B., Pavlov, E. V., & Zakharian, E. (2015). The TRPM8 protein is a testosterone receptor: II. Functional evidence for an ionotropic effect of testosterone on TRPM8. Journal of Biological Chemistry, 290(5), 2670-2688. https://doi.org/10.1074/jbc.M114.610873