%0 Journal Article
%T Structure of the Cardiac Sodium Channel.
%A Jiang D
%A Shi H
%A Tonggu L
%A Gamal El-Din TM
%A Lenaeus MJ
%A Zhao Y
%A Yoshioka C
%A Zheng N
%A Catterall WA
%J Cell
%V 180
%N 1
%D 01 2020 9
%M 31866066
%F 66.85
%R 10.1016/j.cell.2019.11.041
%X 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.