Биофизические механизмы натриевых каналопатий в миокарде: cиндром удлиненного интервала QT и синдром Бругада

Abstract

Mutations in gene SCN5A, which encodes the α-subunit of cardiac voltage-gated sodium channel Nav1.5, are often associated with long QT syndrome type 3 (LQT3) and Brugada syndrome type 1 (BrS1). Recently large progress was achieved in an understanding of biophysical mechanisms of these arrhythmias. The LQT3 syndrome is associated with the gain-of-function due to accelerated activation, decelerated inactivation, appearance of sustained current, and accelerated recovery from inactivation. In contrast, The BrS1 syndrome is associated with loss-of-function due to defective channel trafficking, impaired activation; enhanced fast and slow inactivation, and decelerated recovery from inactivation. Mutations associated with inherited arrhythmias, can also disturb interactions of Nav1.5 with different proteins and/or ligands and cause abnormal reactions in response to pharmacological agents. Furthermore, mutations can affect post-translational modifications and sensitivity to pH and temperature. Here we review current knowledge on biophysical mechanisms of Brugada and long QT syndromes. We focus on limitations of studies that use heterologous expression systems and causes hampering our understanding of genotype-phenotype relations of SCN5A mutations.