Elucidating sodium channel NaV1.5 clustering in cardiac myocytes using super-resolution techniques

Abstract

This editorial refers to ‘Super-resolution imaging reveals that loss of the C-terminus of connexin43 limits microtubule plus-end capture and NaV1.5 localization at the intercalated disc’ by E. Agullo-Pascual et al. , pp. 371–381, this issue. The cardiac voltage-gated sodium channel, NaV1.5, is responsible for conducting the inward sodium current ( I Na), which leads to the fast depolarization of the cardiac cell membrane. Mutations in SCN5A, the gene encoding NaV1.5, that lead to alterations in I Na are linked to many cardiac phenotypes including congenital long QT syndrome type 3, Brugada syndrome, atrial fibrillation, conduction slowing, and dilated cardiomyopathy. Several partner proteins have been described to associate with NaV1.5, and the genes encoding some of these regulatory proteins have also been found to be mutated in patients with inherited forms of cardiac arrhythmias.1 Recent investigations have revealed that the expression level, cellular localization, and activity of NaV1.5 are finely regulated by complex molecular and cellular mechanisms. Multiple pools of NaV1.5 in cardiac cells have been identified,2 depending on where they are targeted and with which partner proteins they interact ( Figure 1A ). Thus, proteins such as SAP97,3 ankyrin-G, plakophilin 2 (PKP2), and connexin43 (Cx43)4,5 have been described to interact with NaV1.5. The importance of these interactions in targeting and stabilizing NaV1.5 at the intercalated disc (ID), where cells are electrically and mechanically coupled, is only partially understood. NaV1.5 is also expressed at the lateral membrane of cardiomyocytes, and its targeting to this compartment is regulated by …