Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

Abstract

Nav1.5 is the predominant cardiac sodium channel subtype, encoded by the SCN5A gene, which is involved in the initiation and conduction of action potentials throughout the heart. Along its biosynthesis process, Nav1.5 undergoes strict genomic and non-genomic regulatory and quality control steps that allow only newly synthesized channels to reach their final membrane destination and carry out their electrophysiological role. These regulatory pathways are ensured by distinct interacting proteins that accompany the nascent Nav1.5 protein along with different subcellular organelles. Defects on a large number of these pathways have a tremendous impact on Nav1.5 functionality and are thus intimately linked to cardiac arrhythmias. In the present review, we provide current state-of-the-art information on the molecular events that regulate SCN5A/Nav1.5 and the cardiac channelopathies associated with defects in these pathways.

Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Nav1.5 downregulation and ventricular arrhythmias

“…These data As the main sodium channel subunit for cardiomyocyte action potential development, Na v 1.5 plays pivotal roles in cardiac conduction. Abnormal Na v 1.5 expression and distribution may exert deficient Na + currents and conduction, which are arrhythmogenic [43]. Reduced Na v 1.5 protein expression after I/R, primarily on cardiomyocyte membrane, prolonged the QRS complex due to deficient conduction and lethal ventricular arrhythmias as previously described [21].…”

Variability in reported midpoints of (in)activation of cardiac INa

“…Use of different cell lines, with different levels of endogenous currents, may cause between-experiment variability, while differing expression levels in each cell could cause within-experiment variability. Finally, several factors including channel glycosylation and phosphorylation regulate I Na in cardiomyocytes (Marionneau and Abriel, 2015; Daimi et al, 2022). While some of these mechanisms may be highly specialised to cardiomyocytes, we might expect some forms of biological regulation even in cells non-natively expressing sodium channels, which could cause any type of variability depending on how the mechanisms themselves vary.…”

“…But should we also expect cell-to-cell or intersubject differences in properties that are not governed by channel count, such as voltage-dependence? Ion channel function is known (or suspected) to be modulated by several mechanisms, including localisation, phosphorylation, stretch, and even proximity to other channels (Marionneau and Abriel, 2015; Daimi et al, 2022; Beyder et al, 2010; Hichri et al, 2020). But what is the impact of such mechanisms on variability in ‘baseline’ currents, measured under controlled experimental conditions?…”

How Functional Genomics Can Keep Pace With VUS Identification

“…These studies should be considered within the context of the complexity of NaV1.5, β-subunits and other binding partners. Pathogenicity may stem from or be modulated by any of these components and even some of the established “gold standard” techniques should be interpreted with caution ( 65 ).…”