Mechanisms and models of cardiac sodium channel inactivation

Shortly after cardiac Na⁺ channels activate and initiate the action potential, inactivation ensues within milliseconds, attenuating the peak Na⁺ current, I_Na, and allowing the cell membrane to repolarize. A very limited number of Na⁺ channels that do not inactivate carry a persistent I_Na, or late I_Na. While late I_Na is only a small fraction of peak magnitude, it significantly prolongs ventricular action potential duration, which predisposes patients to arrhythmia. Here, we review our current understanding of inactivation mechanisms, their regulation, and how they have been modeled computationally. Based on this body of work, we conclude that inactivation and its connection to late I_Na would be best modeled with a “feet-on-the-door” approach where multiple channel components participate in determining inactivation and late I_Na. This model reflects experimental findings showing that perturbation of many channel locations can destabilize inactivation and cause pathological late I_Na.