LAUSR

Nav1.5, the voltage-gated cardiac Na C channel, conducts the inward NaC current (INa), which is the main depolarizing current responsible for initiation and propagation of the cardiac action potential. Mutations in SCN5A, the gene encoding for Nav1.5, have been linked to arrhythmic disorders including type 3 long QT syndrome (LQTS), Brugada Syndrome (BrS), Sudden Infant Death Syndrome (SIDS), progressive conduction defects, and rarely, dilated cardiomyopathy. Genetic deletion of SCN5A in mice is lethal while mice heterozygous for SCN5A are viable but develop progressive conduction defects, underscoring the vital role of this channel in cardiac electrical activity. Nav1.5 is composed of 4 interconnected homologous domains each consisting of 6 transmembrane segments. The a-subunit of Nav1.5, which comprises >2000 amino acids, assembles with a smaller transmembrane b-subunit. Because of the structural complexity and critical role of Nav1.5 in organismal survival, nature has devised multiple layers for its regulation. These include alternative splicing, use of alternative promoters, mRNA editing, and post-translational modifications. Post-translational modifications (PTMs) of Nav1.5 include phosphorylation, palmitoylation, methylation, glycosylation, S-nitrosylation, lipoxidation, and ubiquitinylation. These post-translational modifications regulate cellular trafficking, channel properties, and degradation/internalization of Nav1.5. Furthermore, these modifications, and their dysregulation, lead to significant changes in the amplitude and kinetics of the cardiac sodium current, and may account for Nav1.5-dependent conduction disorders. For example, phosphorylation of Nav1.5 by protein kinase A (PKA) shifts voltage dependence of Nav1.5 steady-state inactivation toward negative potentials, increases Nav1.5 by changing channel trafficking or conductance, and augments the late sodium current. Reflecting these biophysical effects, mutation of the PKA consensus site in Nav1.5 is associated with type 3 LQTS and BrS. Adding to the PTMs of Nav1.5, a recent study showed that Nav1.5 undergoes reversible lysine acetylation regulated by the Sirtuin1 deacetylase. Sirtuin1, a NADC-dependent energy-sensing lysine deacetylase implicated in longevity, deacetylates lysine 1479 in Nav1.5, and by doing so promotes Nav1.5 trafficking to the surface of cardiomyocytes, thus increasing INa . Furthermore, mice lacking cardiac Sirtuin1 die prematurely due to arrhythmias. Nav1.5 is hyperacetylated in ventricular tissues of patients with cardiac conduction “disease underscoring” the clinical significance of Nav1.5 acetylation. Because of the role Sirtuin1 plays in governing the circadian rhythm, and the dependence of Nav1.5 expression on a functional molecular clock, 5 it is tempting to speculate that Sirtuin1-regulated cardiac sodium current through lysine deacetylation of Nav1.5 may have a “circadian pattern as well which may” play a part in the well-described diurnal pattern of cardiac arrhthmias (Fig. 1). In addition, given that the energy metabolite NADC is a co-factor required for Sirtuin1 activity, and is known to regulate INa, 8 this work suggests that Sirtuin1 is the intermediary that links the cellular energetic state to the cardiac action potential.