Biophysical mechanisms of myocardium sodium channelopathies.

Genetic variants of gene SCN5A encoding the alpha-subunit of cardiac voltage-gated sodium channel Nav1.5 are associated with various diseases, including long QT syndrome (LQT3), Brugada syndrome (BrS1), and progressive cardiac conduction disease (PCCD). In the last decades, the great progress in understanding molecular and biophysical mechanisms of these diseases has been achieved. The LQT3 syndrome is associated with gain-of-function of sodium channels Nav1.5 due to impaired inactivation, enhanced activation, accelerated recovery from inactivation or the late current appearance. In contrast, BrS1 and PCCD are associated with the Nav1.5 loss-of-function, which in electrophysiological experiments can be manifested as reduced current density, enhanced fast or slow inactivation, impaired activation, or decelerated recovery from inactivation. Genetic variants associated with congenital arrhythmias can also disturb interactions of the Nav1.5 channel with different proteins or drugs and cause unexpected reactions to drug administration. Furthermore, mutations can affect post-translational modifications of the channels and their sensitivity to pH and temperature. Here we briefly review the current knowledge on biophysical mechanisms of LQT3, BrS1 and PCCD. We focus on limitations of studies that use heterologous expression systems and induced pluripotent stem cells (iPSC) derived cardiac myocytes and summarize our understanding of genotype-phenotype relations of SCN5A mutations.

When the Gates Swing Open Only: Arrhythmia Mutations That Target the Fast Inactivation Gate of Nav1.5.

Nav1.5 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 Nav1.5 (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 Nav1.5 that results in arrhythmia, attempting to correlate the location of the missense mutation to their specific phenotype.