Abstract
The transient receptor potential melastatin subtype 8 (TRPM8) is a nonselective, multimodal ion channel, activated by low temperatures (<28 °C), pressure, and cooling compounds (menthol, icilin). Experimental evidences indicated a role of TRPM8 in cold thermal transduction, different life-threatening tumors, and other pathologies, including migraine, urinary tract dysfunction, dry eye disease, and obesity. Hence, the modulation of the TRPM8 channel could be essential in order to understand its implications in these pathologies and for therapeutic intervention. This short review will cover recent progress on the TRPM8 agonists and antagonists, describing newly reported chemotypes, and their application in the pharmacological characterization of TRPM8 in health and disease. The recently described structures of the TRPM8 channel alone or complexed with known agonists and PIP2 are also discussed.
Highlights
The cold- and menthol-sensitive transient receptor potential melastatin 8 (TRPM8) receptor is a nonselective cation channel, with a certain preference for Ca2+ permeation [1,2]
Experimental evidences indicated a role of transient receptor potential melastatin subtype 8 (TRPM8) in cold thermal transduction, different life-threatening tumors, and other pathologies, including migraine, urinary tract dysfunction, dry eye disease, and obesity
While phosphoinositide PIP2 is a key regulator of channel gating [3,4], testosterone [5], artemin [6,7], and Pirt protein [8] have been proposed as endogenous ligands of TRPM8
Summary
The cold- and menthol-sensitive transient receptor potential melastatin 8 (TRPM8) receptor is a nonselective cation channel, with a certain preference for Ca2+ permeation [1,2]. The upregulation of this channel in different tumors, such as prostate, pancreas, colon, breast, lung, and skin is well documented, and in most cases the expression correlates with tumor aggressiveness [15] While this seems true for initial phases, it has been proposed that TRPM8 could have a protective role in advanced metastatic stages. The TRPM8 receptor could be considered a valuable therapeutic target to develop new active pharmacological treatments for all these pathologies Due to these experimental results on the participation of the TRPM8 channels in the above-mentioned pathologies, it is not surprising that numerous research groups, both academic and pharmaceutical companies, have become interested in the pharmacological modulation of these receptors. This compendium is a follow-up of our previous revision [24], and it is aimed to update the knowledge in the last few years, and to summarize the structural knowledge that have arisen recently, thanks to the advances in electron cryo-microscopy
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
