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

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_V 1.5) 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_V 1.5 channel function by attaching phosphate groups to serine, threonine or tyrosine residues. Phosphorylation of Na_V 1.5 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_V 1.5 channel, (b) formation and subcellular localization of Na_V 1.5 channel macromolecular complex, (c) post-translational phosphorylation and regulation of Na_V 1.5 channel, and (d) how these phosphorylation events of Na_V 1.5 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_V 1.5 channel biology, physiology and pathology, which will also provide an insight into the mechanism of arrythmogenesis at molecular level.