Nav1.5 dysfunction in acquired cardiac disease

Abstract

Alterations in the expression and/or function of the cardiac sodium channel Nav1.5 have been frequently observed in acquired cardiac disease. As mutations in the human gene encoding Nav1.5, SCN5A, have been associated with abnormal cardiac electrophysiology, conduction problems and lethal arrhythmias, the changes in Nav1.5 observed in acquired cardiac disease may contribute to the increased risk for sudden cardiac death. The underlying molecular mechanisms involved in these changes, however, are poorly understood. Nav1.5 is part of a multiprotein complex and as such its function is not only determined by Nav1.5 expression itself but also by e.g. auxiliary β-subunits, components of the cytoskeleton, extracellular matrix proteins, regulatory phosphatases and kinases, glycosylation status and by trafficking proteins. Disruption of the integrity of this protein complex in pathological conditions may lead to alterations in sodium current (INa) density. It is important to understand how disruption of any participant of this multiprotein complex influences Nav1.5 expression and/or function and how this impairs cardiac function. In this review, first the changes observed in Nav1.5 expression and/or function in acquired cardiac disease will be summarized. Then molecular factors will be highlighted whose altered expression affects cardiac Nav1.5 expression and electrophysiology in vivo. Finally, the consequences of these observations will be discussed.