BPS2026 – Heat- and PIP2-dependent TRPM4 activity underlies mutually exclusive human diseases

Transient receptor potential TRPM4 is temperature-sensitive, intracellular calcium-activated, monovalent cations permeable ion channel. It participates in fundamental physiological processes by converting the intracellular calcium increase to membrane depolarization. Gain-of-function (GOF) mutations of TRPM4 cause severe human hereditary diseases of the heart and the skin. Mysteriously, while these mutations are all gain-of-function in nature, some of them selectively affect the heart but not the skin, while others affect the skin without causing heart problems. We found that phosphatidylinositol 4,5-bisphosphate (PIP2) is the key cofactor, which tightly regulates calcium sensitivity of TRPM4. We demonstrated that skin disease-associated TRPM4 mutations relieve the tight control of PIP2, resulting in elevated channel activity but only at the body surface temperature. In contrast, heart disease-associated mutations are known to boost the number of channels, an effect that is annihilated by channel desensitization outside the body core. Indeed, dendritic cells from mice carrying a skin disease mutant exhibited elevated migration at 25–30 o C range compared to those from normal mice, but no difference was observed at 37 o C. These findings shed light on a novel molecular mechanism for dynamic regulation of cellular signaling in physiology and diseases.