TRPM8: From Cold to Cancer, Peppermint to Pain

Temperature perception is vital for cellular and metabolic homeostasis, avoidance, and survival. In the primary afferent nerve terminal, select members of the transient receptor potential (TRP) family of ion channels reside and convert thermal stimuli into neuronal activity. The cold and menthol receptor, TRPM8, is the predominant thermoceptor for cellular and behavioral responses to cold temperatures. Remarkably, this single molecular sensor of cold, that responds at a discrete thermal threshold in vitro (∼28°C), enables sensory afferents to respond to distinct, yet varied thermal thresholds (∼28 to < 5°C). Thus, unlike other thermally-gated TRP channels which are activated at either innocuous or noxious temperatures, TRPM8 provides perception of both pleasantly cool and painfully cold. In addition to this diversity in sensory signaling, TRPM8 has an emerging role in a variety of biological systems, including thermoregulation, cancer, bladder function, and asthma. Here we summarize some key points related to TRPM8 and its potential as a drug target to treat a wide variety of physiological conditions. Nonetheless, it remains to be seen how this single “cool” molecule can serve in such a multitude of biological processes. Keywords: Cold, icilin, menthol, pain, PIP2, prostate cancer, TRPM8, thermoregulation, CMR1, cDNA, TRP channels, Asn934, Cys929, Tyr745, Arg842, Lys856, Gly805, Asp802, Asn799, iPLA2, thio-BCTC, capsazepine, Tyr1005, Leu1009, NGF receptor, bladder urothelium, petrosal ganglia, Xenopus laevis, siRNA, melanoma, breast adenocarcinoma, colorectal cancer, cold allodynia, Cold-induced asthma