Understanding the mechanisms of arrhythmia-linked variants in the disordered regions of Nav1.5

Abstract

The cardiac voltage-gated sodium channel, Nav1.5 initiates excitation in cardiomyocytes. It is a monomer and has four transmembrane repeats (I - IV), each with its own voltage sensing domain (VSD) and connected intracellularly by cytoplasmic linkers. The E428K variant in the DI-DII linker has been linked to sudden cardiac death. The DI-DII inter-domain linker is an intrinsically disordered region (IDR) and its role in channel function is not well understood. It remains unresolved in structures and presents unique research challenges.