title: The TRPM8 protein is a testosterone receptor: II. Functional evidence for an ionotropic effect of testosterone on TRPM8.
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.
authors.affiliation: From the Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, Illinois 61605.
authors.forename: Swapna
authors.initials: S
authors.lastname: Asuthkar
authors.affiliation: From the Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, Illinois 61605.
authors.forename: Lusine
authors.initials: L
authors.lastname: Demirkhanyan
authors.affiliation: From the Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, Illinois 61605.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Sun
authors.affiliation: Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Pia A
authors.initials: PA
authors.lastname: Elustondo
authors.affiliation: the College of Health Sciences, School of Pharmacy, University of Wyoming, Laramie, Wyoming 82071, and.
authors.forename: Vivek
authors.initials: V
authors.lastname: Krishnan
authors.affiliation: the College of Health Sciences, School of Pharmacy, University of Wyoming, Laramie, Wyoming 82071, and.
authors.forename: Padmamalini
authors.initials: P
authors.lastname: Baskaran
authors.affiliation: From the Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, Illinois 61605.
authors.forename: Kiran Kumar
authors.initials: KK
authors.lastname: Velpula
authors.affiliation: the College of Health Sciences, School of Pharmacy, University of Wyoming, Laramie, Wyoming 82071, and.
authors.forename: Baskaran
authors.initials: B
authors.lastname: Thyagarajan
authors.affiliation: Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada, the Department of Basic Sciences, College of Dentistry, New York University, New York, New York 10010.
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Pavlov
authors.affiliation: From the Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, Illinois 61605, zakharel@uic.edu.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Zakharian
mesh_terms: D002118:Calcium / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008051:Lipid Bilayers / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism* / Q000494:pharmacology; D050051:Transient Receptor Potential Channels / Q000378:metabolism
chemical_list: D008051:Lipid Bilayers; D011944:Receptors, Androgen; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D050051:Transient Receptor Potential Channels; D013739:Testosterone; D002118:Calcium
keywords: Androgen; Androgen Receptor; Calcium Channel; Cold and Menthol Receptor TRPM8; Ion Channel; Testosterone; Transient Receptor Potential Channels (TRP Channels)