The TRPM8 protein is a testosterone receptor: I. Biochemical evidence for direct TRPM8-testosterone interactions

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

Research output: Contribution to journalArticle

Abstract

The transient receptor potential ion channel of the melastatin subfamily, TRPM8, is a major cold receptor in the peripheral nervous system. Along with the sensory neurons, the TRPM8 protein is highly expressed in the prostate epithelial cells, and this expression is regulated by androgens. Here we investigated the expression and intracellular localization of the TRPM8 channel in relationship to androgens. We performed experiments using human prostate tissues obtained from healthy individuals and patients with prostate cancer at various stages of the disease as well as in cultured cells. Using an immunohistochemistry approach, we detected an intensive colocalization pattern of the TRPM8 protein with endogenous androgens in all tissues tested, suggesting possible interactions. Co-immunoprecipitation experiments performed using cultured prostate epithelial cells, prostate cancer cells, and HEK-293 cells stably expressing TRPM8 further confirmed direct binding of the steroid hormone, testosterone, to the TRPM8 protein. Applications of picomolar concentrations of testosterone to the primary human prostate cells, endogenously expressing TRPM8, elicited Ca2+responses and channel currents, and those were inhibited in the presence of TRPM8 antagonist, N-(2-aminoethyl)-N-(4-(benzyloxy)-3-methoxybenzyl)thiophene-2-carboxamide hydrochloride. These results indicate that the TRPM8 channel is physically associated with testosterone and suggest that, in addition to a genomic role, testosterone plays a role in direct regulation of the TRPM8 channel function.

Original languageEnglish (US)
Pages (from-to)2659-2669
Number of pages11
JournalJournal of Biological Chemistry
Volume290
Issue number5
DOIs
Publication statusPublished - Jan 30 2015

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Asuthkar, S., Elustondo, P. A., Demirkhanyan, L., Sun, X., Baskaran, P., Velpula, K. K., ... Zakharian, E. (2015). The TRPM8 protein is a testosterone receptor: I. Biochemical evidence for direct TRPM8-testosterone interactions. Journal of Biological Chemistry, 290(5), 2659-2669. https://doi.org/10.1074/jbc.M114.610824