Subcellular diversity of Nav1.5 in cardiomyocytes: distinct functions, mechanisms and targets.

In cardiomyocytes, the rapid depolarisation of the membrane potential is mediated by the α-subunit of the cardiac voltage-gated Na channel (Na 1.5), encoded by the gene SCN5A. This ion channel allows positively charged Na ions to enter the cardiomyocyte, resulting in the fast upstroke of the action potential and is therefore crucial for cardiac excitability and electrical propagation. This essential role is underscored by the fact that dysfunctional Na 1.5 is associated with high risk for arrhythmias and sudden cardiac death. However, development of therapeutic interventions regulating Na 1.5 has been limited due to the complexity of Na 1.5 structure and function and its diverse roles within the cardiomyocyte. In particular, research from the last decade has provided us with increased knowledge on the subcellular distribution of Na 1.5 as well as the proteins which it interacts with in distinct cardiomyocyte microdomains. We here review these insights, detailing the potential role of Na 1.5 within subcellular domains as well as its dysfunction in the setting of arrhythmia disorders. We furthermore provide an overview of current knowledge on the pathways involved in (microdomain-specific) trafficking of Na 1.5, and their potential as novel targets. Unravelling the complexity of Na 1.5 (dys)function may ultimately facilitate the development of therapeutic strategies aimed at preventing lethal arrhythmias. This is not only of importance for pathophysiological conditions where sodium current is specifically decreased within certain subcellular regions, such as in arrhythmogenic cardiomyopathy and Duchenne muscular dystrophy, but also for other acquired and inherited disorders associated with Na 1.5.