When the Gates Swing Open Only: Arrhythmia Mutations That Target the Fast Inactivation Gate of Na_v1.5

Na_v1.5 is the main voltage-gated sodium channel found in cardiac muscle, where it facilitates the fast influx of Na⁺ ions across the cell membrane, resulting in the fast depolarization phase-phase 0 of the cardiac action potential. As a result, it plays a major role in determining the amplitude and the upstroke velocity of the cardiac impulse. Quantitively, cardiac sodium channel activates in less than a millisecond to trigger the cardiac action potential and inactivates within 2-3 ms to facilitate repolarization and return to the resting state in preparation for firing the next action potential. Missense mutations in the gene that encodes Na_v1.5 (SCN5A), change these time constants which leads to a wide spectrum of cardiac diseases ranging from long QT syndrome type 3 (LQT3) to sudden cardiac death. In this mini-review I will focus on the missense mutations in the inactivation gate of Na_v1.5 that results in arrhythmia, attempting to correlate the location of the missense mutation to their specific phenotype.