Heat- and PIP2-dependent TRPM4 activity underlies mutually exclusive human diseases
Abstract
Temperature-sensitive transient receptor potential melastatin subfamily 4 (TRPM4) ion channels convert intracellular calcium increases into membrane depolarization, thereby linking these two powerful cellular signaling pathways in diverse physiological processes. TRPM4 mutations cause severe human hereditary cardiovascular and skin diseases; mysteriously, while these mutations are gain-of-function in nature, they affect the heart and the skin in a mutually exclusive manner. Here, we show that phosphatidylinositol 4,5-bisphosphate (PIP2) lipid is a required cofactor for TRPM4 activity by tightly regulating its calcium sensitivity. We detected two PIP2 binding sites and located the high-affinity site adjacent to the S4-S5 linker. 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 diseases are associated with mutations known to boost the number of channels, an effect we found to be annihilated by channel desensitization outside the body core. Indeed, dendritic cells from transgenic mice carrying a skin disease mutant exhibited elevated migration at 25-to-30°C range compared to those from normal mice, but no difference was observed at 37°C. These findings shed light on a molecular mechanism for dynamic regulation of cellular signaling in physiology and diseases.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Yuhua Tian
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania
Soohyeon Bae
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Xuesong Wu
Department of Chemistry and Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, iChEM
Kyle C. Rouen
Department of Physiology and Membrane Biology, School of Medicine, University of California
Adriana Hernández-González
Department of Physiology and Membrane Biology, University of California Davis
Yanxiao Han
Department of Physiology and Membrane Biology, School of Medicine, University of California
Abdullah Al Tekreeti
Department of Physiology and Membrane Biology, School of Medicine, University of California
Simon Vu
Department of Physiology and Membrane Biology, School of Medicine, University of California
Irene Chen
Department of Molecular and Cell Biology, University of California
Ellen Li
Carlmont High School
Igor Vorobyov
Department of Physiology and Membrane Biology, School of Medicine, University of California
Vladimir Yarov-Yarovoy
Department of Physiology and Membrane Biology, University of California Davis
Byung-Chang Suh
Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology
Samuel T. Hwang
Department of Dermatology, University of California Davis
Jie Zheng
Key Laboratory of Radiation Physics and Technology, Ministry of Education, Institute of Nuclear Science and Technology