The cardiac CaMKII-Na_v1.5 relationship: From physiology to pathology

The SCN5A gene encodes Na_v1.5, which, as the cardiac voltage-gated Na⁺ channel's pore-forming α subunit, is crucial for the initiation and propagation of atrial and ventricular action potentials. The arrhythmogenic propensity of inherited SCN5A mutations implicates the Na⁺ channel in determining cardiomyocyte excitability under normal conditions. Cytosolic kinases have long been known to alter the kinetic profile of Na_v1.5 inactivation via phosphorylation of specific residues. Recent substantiation of both the role of calmodulin-dependent kinase II (CaMKII) in modulating the properties of the Na_v1.5 inactivation gate and the significant rise in oxidation-dependent autonomous CaMKII activity in structural heart disease has raised the possibility of a novel pathway for acquired arrhythmias - the CaMKII-Na_v1.5 relationship. The aim of this review is to: (1) outline the relationship's translation from physiological adaptation to pathological vicious circle; and (2) discuss the relative merits of each of its components as pharmacological targets.