Structure of the Cardiac Sodium Channel

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. [Display omitted] •The structure of the cardiac sodium channel reveals key functional features•The antiarrhythmic drug flecainide blocks the pore below the selectivity filter•The ion selectivity filter and inactivation gate are revealed in atomic detail•An arrhythmia mutation creates a pathogenic gating pore ∼2 Å in diameter The high-resolution structure of the cardiac sodium channel gives detailed insights into voltage-dependent activation, ion selectivity, arrhythmia mechanisms, and antiarrhythmic drug action at the atomic level.