A revised view of cardiac sodium channel "blockade" in the long-QT syndrome

Mutations in SCN5A, encoding the cardiac sodium (Na) channel, are linked to a form of the congenital long-QT syndrome (LQT3) that provokes lethal vent ricular arrhythmias. These autosomal dominant mutations disrupt Na channel function, inhibiting channel inactivation, thereby causing a sustained ioni c current that delays cardiac repolarization. Sodium channel-blocking antia rrhythmics, such as lidocaine, potently inhibit this pathologic Na current (I-Na) and are being evaluated in patients with LQT3. The mechanism underly ing this effect is unknown, although high-affinity "block" of the open Na c hannel pore has been proposed. Here we report that a recently identified LQ T3 mutation (R1623Q) imparts unusual lidocaine sensitivity to the Na channe l that is attributable to its altered functional behavior. Studies of lidoc aine on individual R1623Q single-channel openings indicate that the open-ti me distribution is not changed, indicating the drug does not block the open pore as proposed previously. Rather, the mutant channels have a propensity to inactivate without ever opening ("closed-state inactivation"), and lido caine augments this gating behavior. An allosteric gating model incorporati ng closed-state inactivation recapitulates the effects of lidocaine on path ologic I-Na These findings explain the unusual drug sensitivity of R1623Q a nd provide a general and unanticipated mechanism for understanding how Na c hannel-blocking agents may suppress the pathologic, sustained Na current in duced by LQT3 mutations.