Targeting the sodium channel NaV1.5 to specific membrane compartments of cardiac cells: not a simple task!

Abstract

Cardiac cells, also called cardiomyocytes, are cells that are similar to neurons and epithelial cells in that they harbor specific membrane compartments. In this sense, these cells can be seen as polarized cells.1 There are 2 main regions of the cardiomyocyte: (1) the intercalated disc (ID), which is a domain containing specialized cell–cell junction molecules and (2) the lateral membrane that comprise membrane invaginations called t-tubules (Figure). Typical ventricular myocytes are rod-shaped, about 100-μm long, with a width of 20 μm. The IDs are located at the ends of the cells along the 20-μm width. This cellular architecture is important for both the mechanical function of these cells and also the directional spread of cardiac electric activity. Figure. The different NaV1.5 channel pools in cardiomyocytes . Depending on the partner proteins they interact with, NaV1.5 is found either at the intercalated disc region, or at the lateral membrane (composed of crest regions and T-tubules) of cardiomyocytes. One should note that along the crests, functional sodium channels do not distribute homogenously, but segregate in densely populated clusters (as demonstrated in Bhargava et al15), coexisting with areas devoid of functional channels. Article, see p 929 A myriad of membrane proteins, among them ion channels, have been found to be specifically expressed in distinct membrane domains of the cardiomyocyte. These proteins are the molecular determinants of cell polarization. It seems obvious that the precise localization to specific membrane domains is related to distinct functional roles. The cardiac sodium channel, NaV1.5, encoded by the gene SCN5A , has received a lot of attention in the past 2 decades.2 This is mainly resulting from the reports of hundreds of mutations in its gene that were found in patients with specific arrhythmic syndromes, such as congenital long-QT and …