Dysfunctional Nav1.5 channels due to SCN5A mutations

Abstract

The voltage-gated sodium channel 1.5 (Nav1.5), encoded by the SCN5A gene, is responsible for the rising phase of the action potential of cardiomyocytes. The sodium current mediated by Nav1.5 consists of peak and late components (I and I). Mutant Nav1.5 causes alterations in the peak and late sodium current and is associated with an increasingly wide range of congenital arrhythmias. More than 400 mutations have been identified in the SCN5A gene. Although the mechanisms of SCN5A mutations leading to a variety of arrhythmias can be classified according to the alteration of I and I as gain-of-function, loss-of-function and both, few researchers have summarized the mechanisms in this way before. In this review article, we aim to review the mechanisms underlying dysfunctional Nav1.5 due to SCN5A mutations and to provide some new insights into further approaches in the treatment of arrhythmias. Impact statement The field of ion channelopathy caused by dysfunctional Nav1.5 due to SCN5A mutations is rapidly evolving as novel technologies of electrophysiology are introduced and our understanding of the mechanisms of various arrhythmias develops. In this review, we focus on the dysfunctional Nav1.5 related to arrhythmias and the underlying mechanisms. We update SCN5A mutations in a precise way since 2013 and presents novel classifications of SCN5A mutations responsible for the dysfunction of the peak (I) and late (I) sodium channels based on their phenotypes, including loss-, gain-, and coexistence of gain- and loss-of function mutations in I, I, respectively. We hope this review will provide a new comprehensive way to better understand the electrophysiological mechanisms underlying arrhythmias from cell to bedside, promoting the management of various arrhythmias in practice.

Acquired long QT syndrome in chronic kidney disease patients

“…In addition, the Na þ /Ca 2þ exchanger (NCX) also plays a prominent role in modulating the APD in myocytes in failing hearts [58]. Late I Na is an integral part of the sodium current, which persists long after the fast-inactivating component and could contribute to the prolongation of the APD [59]. Late I Na is significantly increased in myocardial cells from failing human hearts and selected inhibition of late I Na is effective in shortening the QT interval and reducing ventricular arrhythmogenic activity [60].…”

“…Enhanced I Na-L can be observed in acquired conditions, such as hypertrophic cardiomyopathy, heart failure and drug-induced arrhythmias [112,113]. Mexiletine, a Vaughan-Williams class Ib antiarrhythmic agent, can shorten the APD by selectively suppressing I Na-L without affecting QRS duration [59]. We once reported that 12 patients with refractory TdP secondary to aLQTS were treated with oral mexiletine, 150-450 mg/day orally.…”

NAD+ Metabolism as an Emerging Therapeutic Target for Cardiovascular Diseases Associated With Sudden Cardiac Death

“…Cardiac sodium current (I Na ) upstroke during depolarization phase is predominantly mediated by Na v 1.5 channel, which is the major voltage-gated sodium channel in the heart (Veerman et al, 2015). Mutations in Na v 1.5 are associated with a number of cardiac diseases such as long QT syndrome, AF and cardiomyopathy (Song and Shou, 2012;Shy et al, 2013;Han et al, 2018;Wilde and Amin, 2018). Matasic et al (2020) showed that NR increased I Na and reduced residual late I Na in vitro, and more importantly administration of NR decreased QTc in vivo.…”

Potential roles of GATA binding protein 5 in cardiovascular diseases

“…Additionally, GATA4 and GATA5 bind to the same binding region of the sodium voltage-gated channel alpha subunit 5 (SCN5A) gene promoter and co-activate the transcription of SCN5A gene (Tarradas et al, 2017). Mutations in the SCN5A gene cause a va-riety of arrhythmias, including Brudaga syndrome, long QT syndrome 3, sick sinus syndrome, cardiac conduction disease, progressive cardiac conduction defect and AF (Han et al, 2018). The SCN5A gene (chromosome 3p21) encodes the alpha subunit of the voltage-gated sodium channel 1.5 (Nav1.5) (Verkerk et al, 2018).…”

“…GATA4, GATA5 and GATA6 maintain the expression of NKX2-5 by activating cx36.7 (Miyagi et al, 2016), the expression of NKX2-5 can directly up-regulate the expression of the Hes-related family basic helix-loop-helix (bHLH) transcription factor with YRPW motif 2 (HEY2), SCN5A and other genes (Anderson et al, 2018). SCN5A is closely related to arrhythmia (Han et al, 2018). Of note, HEY2 is a member of the bHLH transcription inhibitor family, the non-synonymous mutations of HEY2 are related to cardiac malfor-mations, such as congenital ventricular septal defect (Fardoun et al, 2019).…”