Structure of the Cardiac Sodium Channel.

Abstract

Voltage-gated sodium channel Na_v1.5 generates cardiac action potentials and initiates the heartbeat. Here, we report structures of Na_V1.5 at 3.2-3.5 Å resolution. Na_V1.5 is distinguished from other sodium channels by a unique glycosyl moiety and loss of disulfide-bonding capability at the Na_Vβ 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 Na_v1.5 structure, pharmacology, activation, inactivation, ion selectivity, and arrhythmias.