Structural basis of cytoplasmic nav1.5 and nav1.4 regulation

Sara Nathan, Sandra B. Gabelli, Jesse B. Yoder, Lakshmi Srinivasan, Richard W. Aldrich, Gordon F. Tomaselli, Manu Ben-Johny, L. Mario Amzel

Research output: Contribution to journalReview articlepeer-review

6 Scopus citations

Abstract

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 NaVsbysingle-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.

Original languageEnglish (US)
Article numbere202012722
JournalJournal of General Physiology
Volume153
Issue number1
DOIs
StatePublished - Jan 4 2021

ASJC Scopus subject areas

  • Physiology

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