Open AccessStructural basis of cytoplasmic NaV1.5 and NaV1.4 regulation
Author(s) -
Sara Nathan,
Sandra B. Gabelli,
Jesse Yoder,
Lakshmi Srinivasan,
Richard W. Aldrich,
Gordon F. Tomaselli,
Manu Ben-Johny,
L.M. Amzel
Publication year - 2020
Publication title -
the journal of general physiology/the journal of general physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.064
H-Index - 127
eISSN - 1540-7748
pISSN - 0022-1295
DOI - 10.1085/jgp.202012722
Subject(s) - cytoplasm , gene isoform , nav1.5 , sodium channel , nav1 , transmembrane protein , biophysics , calmodulin , microbiology and biotechnology , cryo electron microscopy , ion channel , endoplasmic reticulum , chemistry , biology , biochemistry , sodium , receptor , organic chemistry , gene , enzyme
Voltage-gated sodium channels (NaVs) are membrane proteins responsible for the rapid upstroke of the action potential in excitable cells. There are nine human voltage-sensitive NaV1 isoforms that, in addition to their sequence differences, differ in tissue distribution and specific function. This review focuses on isoforms NaV1.4 and NaV1.5, which are primarily expressed in skeletal and cardiac muscle cells, respectively. The determination of the structures of several eukaryotic NaVs by single-particle cryo-electron microscopy (cryo-EM) has brought new perspective to the study of the channels. Alignment of the cryo-EM structure of the transmembrane channel pore with x-ray crystallographic structures of the cytoplasmic domains illustrates the complementary nature of the techniques and highlights the intricate cellular mechanisms that modulate these channels. Here, we review structural insights into the cytoplasmic C-terminal regulation of NaV1.4 and NaV1.5 with special attention to Ca2+ sensing by calmodulin, implications for disease, and putative channel dimerization.