Testosterone is a Highly Potent and Specific Agonist of TRPM8

Abstract

The role of the TRPM8 channel in the peripheral nervous system as a major receptor for cold temperatures has been well established. Less certainty was gained about the role of the channel beyond the nervous system. Particularly, the presence and high expression levels of TRPM8 in the prostate epithelium were not well understood. Recently, we identified that the prevalent male hormone, testosterone, is a highly potent endogenous agonist of TRPM8 channels. Picomolar concentrations of testosterone elicited rapid Ca2+-uptake in cells expressing TRPM8, including prostate epithelial cells and neurons. Furthermore, testosterone evoked openings of the purified TRPM8 channel in planar lipid bilayers that were promptly inhibited with TRPM8 antagonists, or the purified androgen receptor (AR) protein. In the bilayers, TRPM8 activity was induced by both, permeable testosterone, as well as an impermeable analog, testosterone covalently conjugated to BSA. Interestingly, BSA-testosterone evoked openings of TRPM8 only into a small conductance state, with a mean slope conductance of ∼7 pS, in comparison to ∼37 pS obtained with the permeable analog. Furthermore, the prevalent female hormones, estradiol and progesterone, had no effect on the channel at picomolar or nanomolar concentrations, and only exerted openings at micromolar concentrations, but even then these steroids could open TRPM8 only into a small conductance state of ∼8 pS. These results indicate that binding of steroids to the extracellular site induces conformational changes of the channel resulting in a narrow permeation path. Together, our results demonstrate that testosterone is not only a highly potent but also a highly specific agonist of TRPM8.