The TRPM8 Protein is a Testosterone Receptor. Part II: Functional Evidence for an Ionotropic Effect of Testosterone on TRPM8 [Cell Biology]

December 5th, 2014 by Asuthkar, S., Demirkhanyan, L., Sun, X., Elustondo, P., Krishnan, V., Baskaran, P., Velpula, K. K., Thyagarajan, B., Pavlov, E., Zakharian, E.

Testosterone is a key steroid hormone in the development of male reproductive tissues and the regulation of the central nervous system. Rapid signaling mechanism induced by testosterone affects numerous behavioral traits, including sexual drive, aggressiveness, or fear conditioning. However, the currently identified testosterone receptor(s) are 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 know 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, prostate cancer cells PC3, dorsal root ganglion (DRG) 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 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.