The Emerging Pharmacology of TRPM8 Channels: Hidden Therapeutic Potential Underneath a Cold Surface

Transient receptor potential melastatin 8 (TRPM8) is a non-selective cation channel activated by cold temperature and cooling agents. TRPM8 is expressed in a subpopulation of cold-sensitive sensory neurons, as well as in the male urogenital system. TRPM8 is markedly upregulated in prostate cancer and in other tumors such as breast adenocarcinoma and melanoma. Moreover, recent studies suggest the potential involvement of TRPM8 channels in the pathophysiology of cold nociception and cold allodynia. This has led to a strong interest in the pursuit of novel modulators of TRPM8 channels. This review highlights our current knowledge of TRPM8 pharmacology and modulation mechanisms, detailing structural features important for TRPM8 gating by different agonists, the mechanism of antagonism by different compounds and the potential relevance of TRPM8 for treatment of various pathological conditions. Keywords: Cold, thermoreceptor, menthol, pain, prostate cancer, TRPM8 Channels, Transient receptor potential melastatin, breast adenocarcinoma, melanoma, cold nociception, cold allodynia, human prostate carcinoma, prostate epithelium, peripheral sensory neurons, TRPM8 modulators, TRPM8 gene, voltage-gated potassium (Kv) channels, putative phosphorylation sites, bladder urothelium, male urogenital tract, unmyelinated afferents, detrusor overactivity, neuroendocrine tumor, rat myocytes, vasomotor responses, trigeminal ganglia, TRPM8-expressing neurons, C-fibers, A fibers, S4-S5 linker, menthol affinity, Tyr745, Asp802, desensitization, voltage clamp errors, Calcium Imaging Microscopy, Patch-Clamp Electrophysiology, MWCmodel, WS-12, citronellal, geraniol, linalool, TRPM8 agonist, Leu1009, TRPV1, SKF96365, AMTB, Y745H mutant, HEK293 cells, hippocampal neurons, DRG neurons, Ser9, Thr17