TRPM8 acute desensitization is mediated by calmodulin and requires PIP(2): distinction from tachyphylaxis.

The cold-sensing channel transient receptor potential melastatin 8 (TRPM8) features Ca(2+)-dependent downregulation, a cellular process underlying somatosensory accommodation in cold environments. The Ca(2+)-dependent functional downregulation of TRPM8 is manifested with two distinctive phases, acute desensitization and tachyphylaxis. Here we show in rat dorsal root ganglion neurons that TRPM8 acute desensitization critically depends on phosphatidylinositol 4,5-bisphosphate (PIP(2)) availability rather than PIP(2) hydrolysis and is triggered by calmodulin activation. Tachyphylaxis, on the other hand, is mediated by phospholipase hydrolysis of PIP(2) and protein kinase C/phosphatase 1,2A. We further demonstrate that PIP(2) switches TRPM8 channel gating to a high-open probability state with short closed times. Ca(2+)-calmodulin reverses the effect of PIP(2), switching channel gating to a low-open probability state with long closed times. Thus, through gating modulation, Ca(2+)-calmodulin provides a mechanism to rapidly regulate TRPM8 functions in the somatosensory system.