Mechanisms of expression, trafficking and biophysical activity regulation of voltage-gated cardiac sodium channels

Genetic variants in the SCN5A gene, encoding the cardiac isoform of the Na V 1.5 voltage-gated sodium channel, were observed in patients with various hereditary heart diseases. Actual problems of modern electrophysiology covers the search for mechanisms of the disease development and the search for approaches to correct sodium current dysfunction in pathological conditions. In recent decades, significant progress has been achieved in understanding the life cycle of Na V 1.5 and the distribution of channels in various microdomains of the plasma membrane. Na V 1.5 is regulated at all possible levels from SCN5A expression to control of ubiquitin-dependent degradation. Depending on the microdomain of the plasma membrane, Na V 1.5 is part of various macromolecular complexes. Thus, in the lateral membrane, Na V 1.5 is co-localized with the dystrophin-syntrophin complex, and in the region of the intercalated disc, sodium channels are surrounded by desmosomal proteins, G-ankyrin, and gap junction proteins. This review systematizes knowledge about Na V 1.5 protein partners in different regions of the cardiomyocyte membrane, as well as about post-translational modifications of Na V 1.5. Special attention is paid to potential clinical applications. Therapy strategies targeting SCN5A synthesis, Na V 1.5 transport, and late sodium current are considered. Thus, the study of the mechanisms regulating the functioning of α-Na V 1.5 in the future will play an important role not only in understanding the biology and pathophysiology of Na V 1.5, but also in the search for new promising methods of therapy.