Life Cycle of the Cardiac Voltage-Gated Sodium Channel NaV1.5.

Caijuan Dong,Ya Wang,Aiqun Ma,Tingzhong Wang

doi:10.3389/fphys.2020.609733

Abstract

Cardiac voltage-gated sodium channel NaV1.5, encoded by SCN5A, is crucial for the upstroke of action potential and excitation of cardiomyocytes. NaV1.5 undergoes complex processes before it reaches the target membrane microdomains and performs normal functions. A variety of protein partners are needed to achieve the balance between SCN5A transcription and mRNA decay, endoplasmic reticulum retention and export, Golgi apparatus retention and export, selective anchoring and degradation, activation, and inactivation of sodium currents. Subtle alterations can impair NaV1.5 in terms of expression or function, eventually leading to NaV1.5-associated diseases such as lethal arrhythmias and cardiomyopathy.

Highlights

The cardiac voltage-gated sodium channel NaV1.5 is made up of a 220-kDa pore-forming α-subunit and 30-kDa auxiliary β-subunits
The aim of this review is to provide an updated account of the life cycle of NaV1.5, while summarizing SCN5A-related diseases and novel therapeutic strategies targeting NaV1.5
Conformational modifications in the following three domains drive the slow inactivation process: the trans-membrane segment S4/D4, the loop between S5-S6/DII (P-loop/DII), and segment S6/DII (Detta et al, 2015).When NaV1.5 channels do not completely inactivate, a lasting current less than 0.5% of the peak current can be detected in the cardiomyocytes, which is known as late INa (INa-L)

Summary

Introduction

The cardiac voltage-gated sodium channel NaV1.5 is made up of a 220-kDa pore-forming α-subunit and 30-kDa auxiliary β-subunits. The SCN5A gene, found on chromosome 3p21, encodes the NaV1.5 channel, which includes four homologous domains (DI-DIV), a C-terminus, and an N-terminus (Figure 1). Each domain of the NaV1.5 channel is composed of six membranespanning segments (S1-S6). The S5 and S6 transmembrane segments form a pore with the intermembrane P-loop, which determines ion selectivity and influx (Jiang et al, 2020). The NaV1.5 channel mediates the rapid influx of sodium ions (Na+), which triggers cardiac action potential (AP), induces rapid depolarization, and initiates the excitation-contraction coupling cascades in the cardiomyocytes (Han et al, 2018). Β1-β4 subunits, encoded by the SCN1b-4b genes, consist of an extracellular N-terminus, a transmembrane α-helix, and an intracellular C terminus (Salvage et al, 2020). The β-subunits act as gating modulators of NaV1.5 and facilitate NaV1.5 residence at the intercalated disk

Objectives

Findings

Conclusion