Potential Role of TRPM8 in Cold-Induced Hypertension and Its Clinical Implications

Seasonal variation in blood pressure that is higher in winter and lower in summer has been attributed to several factors that include changes in the activity of autonomic nervous system, vasopressin and expression of endothelial nitric oxide synthase (eNOS). Transient receptor potential melastatin 8 (TRPM8), a non-selective Ca2+-permeable cationic channel, serves as a molec-ular transducer to sense cold by the somatosensory system. TRPM8 is sensitive to protein kinase C (PKC) and phosphatidyl inositol-4,5-biphosphate [PI(4,5)P2] suggesting that TRPM8 is stimulated by phospholipase C (PLC)-coupled receptors. Acti-vated PLC inhibits TRPM8 by reducing cellular PI(4,5)P2 levels and by activating PKC via diacyl glycerol. Bradykinin and prostaglandin E2 (PGE2), which are pro-inflammatory molecules, reduce the responses to cold, suggesting that phospholipase A2 (PLA2), which releases polyunsaturated fatty acids (PUFAs), the precursors of various eicosanoids, from the cell membrane lipid pool can modulate the function of TRPM8. TRPM8 functions as a nociceptor and modulates immune response. These and other studies indicate that cold-induced activation of transient receptor potential melastatin 8 (TRPM8) plays a role in the pathobiology of hypertension, preeclampsia and in the regulation of inflammation and immunity.