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

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          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.

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          Author and article information

          Journal
          J. Biol. Chem.
          The Journal of biological chemistry
          1083-351X
          0021-9258
          Jan 30 2015
          : 290
          : 5
          Affiliations
          [1 ] From the Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, Illinois 61605.
          [2 ] Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
          [3 ] the College of Health Sciences, School of Pharmacy, University of Wyoming, Laramie, Wyoming 82071, and.
          [4 ] Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada, the Department of Basic Sciences, College of Dentistry, New York University, New York, New York 10010.
          [5 ] From the Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, Illinois 61605, zakharel@uic.edu.
          Article
          M114.610873
          10.1074/jbc.M114.610873
          25480785
          85217f56-f731-4667-aa2d-7472dff153cc
          © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
          History

          Androgen,Androgen Receptor,Calcium Channel,Cold and Menthol Receptor TRPM8,Ion Channel,Testosterone,Transient Receptor Potential Channels (TRP Channels)

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