Title: Structure of the Cardiac Sodium Channel.

Authors: Daohua Jiang, Hui Shi, Lige Tonggu, Tamer M Gamal El-Din, Michael J Lenaeus, Yan Zhao, Craig Yoshioka, Ning Zheng, William A Catterall

Journal, date & volume: Cell, 2020Jan09, 180, 122-134.e10

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/31866066

Abstract
Voltage-gated sodium channel Nav1.5 generates cardiac action potentials and initiates the heartbeat. Here, we report structures of NaV1.5 at 3.2-3.5 Å resolution. NaV1.5 is distinguished from other sodium channels by a unique glycosyl moiety and loss of disulfide-bonding capability at the NaVβ subunit-interaction sites. The antiarrhythmic drug flecainide specifically targets the central cavity of the pore. The voltage sensors are partially activated, and the fast-inactivation gate is partially closed. Activation of the voltage sensor of Domain III allows binding of the isoleucine-phenylalanine-methionine (IFM) motif to the inactivation-gate receptor. Asp and Ala, in the selectivity motif DEKA, line the walls of the ion-selectivity filter, whereas Glu and Lys are in positions to accept and release Na+ ions via a charge-delocalization network. Arrhythmia mutation sites undergo large translocations during gating, providing a potential mechanism for pathogenic effects. Our results provide detailed insights into Nav1.5 structure, pharmacology, activation, inactivation, ion selectivity, and arrhythmias.