Phosphorylation of cardiac voltage‐gated sodium channel: Potential players with multiple dimensions

Abstract

Cardiomyocytes are highly coordinated cells with multiple proteins organized in micro domains. Minor changes or interference in subcellular proteins can cause major disturbances in physiology. The cardiac sodium channel (Na _V1.5) is an important determinant of correct electrical activity in cardiomyocytes which are localized at intercalated discs, T‐tubules and lateral membranes in the form of a macromolecular complex with multiple interacting protein partners. The channel is tightly regulated by post‐translational modifications for smooth conduction and propagation of action potentials. Among regulatory mechanisms, phosphorylation is an enzymatic and reversible process which modulates Na _V1.5 channel function by attaching phosphate groups to serine, threonine or tyrosine residues. Phosphorylation of Na _V1.5 is implicated in both normal physiological and pathological processes and is carried out by multiple kinases. In this review, we discuss and summarize recent literature about the (a) structure of Na _V1.5 channel, (b) formation and subcellular localization of Na _V1.5 channel macromolecular complex, (c) post‐translational phosphorylation and regulation of Na _V1.5 channel, and (d) how these phosphorylation events of Na _V1.5 channel alter the biophysical properties and affect the channel during disease status. We expect, by reviewing these aspects will greatly improve our understanding of Na _V1.5 channel biology, physiology and pathology, which will also provide an insight into the mechanism of arrythmogenesis at molecular level.