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_Na-P and I_Na-L). 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_Na-P and I_Na-L 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_Na-P) and late (I_Na-L) sodium channels based on their phenotypes, including loss-, gain-, and coexistence of gain- and loss-of function mutations in I_Na-P, I_Na-L, 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.

Keywords: INa-L; INa-P; Nav1.5; SCN5A; gain-of-function; loss-of-function.

Figure 1.

Updated SCN5A mutations identified from 2013 to present. The red represents gain of I_Na-P, blue represents gain of I_Na-L, green represents loss of I_Na-P, yellow represents loss of I_Na-L, the mixed colors represent coexistence of gain- and loss-of-function mutations. (A color version of this figure is available in the online journal.)

Figure 2.

The ion mechanism of gain of function of I_Na-L leading to arrhythmia.

Figure 3.

The ion mechanism of loss of function of I_Na-L leading to arrhythmia.