Analysis of Slow Inactivation of Nav1.5 Channels in the Development of Hereditary Heart Pathology

Abstract

Cardiac voltage-gated Na_v1.5 sodium channels are responsible for initiation and propagation of action potentials in cardiomyocytes. Na_v1.5 dysfunction may be due to both pathogenic variants in the gene itself SCN5A, encoding Na_v1.5, and genetic variants in the genes of other proteins that regulate its activity and transport. The change of different phases of the action potential is determined by the strict temporal organization of activation and inactivation of various ion channels. Transitions between functional states of the channel, including the transition to the slow inactivation state, can be influenced by a variety of factors and proteins interacting with the channel. Despite the fact that the process of slow inactivation of the channel has been known for several decades, its role in the mechanism of development of hereditary heart pathology remains unclear. In this work, using the method of local potential fixation (patch clamp) in a lead from a whole cell, we investigated changes in the process of slow inactivation of Na_v1.5 under the influence of various mutations in structural genes (DSP-H1684R, LMNA-R249Q, FLNC-R1267Q, and FLNC-V2264M), associated with genetically determined myocardial pathology, leading to dysfunction of cardiomyocytes. We used a model of cardiomyocytes differentiated from induced pluripotent stem cells (CM-iPSCs) and demonstrated enhancement of slow channel inactivation in a model of CM-iPSCs obtained from patients with a cardiomyopathy phenotype combined with ventricular arrhythmias. Thus, the presented work contributes to understanding the role of the process of slow inactivation of Na_v1.5 in the mechanism of development of heart pathology.