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 (NaV1.5), 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 NaV1.5 is associated with high risk for arrhythmias and sudden cardiac death. However, development of therapeutic interventions regulating NaV1.5 has been limited due to the complexity of NaV1.5 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 NaV1.5 as well as the proteins which it interacts with in distinct cardiomyocyte microdomains. We here review these insights, detailing the potential role of NaV1.5 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 NaV1.5, and their potential as novel targets. Unravelling the complexity of NaV1.5 (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 NaV1.5. figure legend Overview of NaV1.5 interacting proteins, putative function and associated conditions in lateral membrane versus intercalated disc, in addition to (future) research areas.