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From Proteopedia
Human TRPM4 ion channel in lipid nanodiscs in a calcium-free state
Structural highlights
Disease[TRPM4_HUMAN] Familial progressive cardiac conduction defect;Brugada syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function[TRPM4_HUMAN] Calcium-activated non selective (CAN) cation channel that mediates membrane depolarization. While it is activated by increase in intracellular Ca(2+), it is impermeable to it. Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane. It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. Participates in T-cell activation by modulating Ca(2+) oscillations after T lymphocyte activation, which is required for NFAT-dependent IL2 production. Involved in myogenic constriction of cerebral arteries. Controls insulin secretion in pancreatic beta-cells. May also be involved in pacemaking or could cause irregular electrical activity under conditions of Ca(2+) overload. Affects T-helper 1 (Th1) and T-helper 2 (Th2) cell motility and cytokine production through differential regulation of calcium signaling and NFATC1 localization. Enhances cell proliferation through up-regulation of the beta-catenin signaling pathway.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedTransient receptor potential (TRP) melastatin 4 (TRPM4) is a widely expressed cation channel associated with a variety of cardiovascular disorders. TRPM4 is activated by increased intracellular calcium in a voltage dependent manner, but unlike many other TRP channels is permeable to monovalent cations only. Here we present two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3A resolution as determined by single particle electron cryo-microscopy. These structures, with and without calcium bound, reveal a general architecture for this major subfamily of TRP channels and a well-defined calcium binding site within the intracellular side of the S1-S4 domain. The structures correspond to two distinct closed states. Calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening. Structure of the human TRPM4 ion channel in a lipid nanodisc.,Autzen HE, Myasnikov AG, Campbell MG, Asarnow D, Julius D, Cheng Y Science. 2017 Dec 7. pii: science.aar4510. doi: 10.1126/science.aar4510. PMID:29217581[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Asarnow, D | Autzen, H E | Campbell, M G | Cheng, Y | Julius, D | Myasnikov, A G | Membrane protein | Trp channel | Trpm channel | Trpm4
