Atrial Fibrillation and SCN5A Variants

Abstract

Although atrial fibrillation (AF) is clinically and genetically a highly heterogeneous disease, recent studies suggest that the arrhythmia may arise because of interactions between genetic and acquired risk factors - the so called "double-hit" hypothesis. Genome-wide association studies have identified common AF susceptibility loci, and linkage analysis and candidate gene approaches have identified mutations in genes that encode for cardiac ion channels and signaling proteins; however, most of the heritability of AF still remains unexplained. The voltage-dependent cardiac sodium channel, encoded by SCN5A, conducts the main cardiac inward sodium current (I_Na) and is responsible for the upstroke of the atrial action potential. Mutations in SCN5A, which encodes the α-subunit of the Na_V1.5 channel, have been linked with increased susceptibility to not only AF but also ventricular arrhythmias (long QT syndrome, Brugada syndrome), progressive cardiac conduction disease, and overlap syndromes with mixed arrhythmia phenotypes. Over the last decade, functional characterization of SCN5A mutations by expressing the channel in heterologous expression systems and applying cellular electrophysiological techniques has not only advanced our understanding of molecular mechanisms of AF but also potentially identified a mechanism-based approach to treating this common and morbid condition.

Keywords: SCN5A; SCN5A mutations; action potential; atrial fibrillation; electrophysiology; gain of function; loss of function; “two-hit” hypothesis.

Figure 1

The relationship between ionic currents and the duration of the atrial action potential (AP). The AP is initiated by a rapid influx of Na+ ions (phase 0), followed by an early (phase 1 and 2) and late (phase 3) phases of repolarization, before returning to the resting membrane potential (phase 4). * Function-modifying subunit. ‡ Mutations in this gene were associated with atrial fibrillation. (From Darbar D, Roden DM. Genetic mechanisms of atrial fibrillation: impact on response to treatment. Nat Rev Cardiol 2013;10(6):317-29).

Figure 2

Schematic representation of the α and β subunits of the voltage-gated sodium channel. The four homologous domains (I-IV) of the α subunit are represented; S5 and S6 are the pore-lining segments and S4 is the core of the voltage-sensor. In the cytoplasmic linker between domains III and IV the IFMT (isoleucine, phenylalanine, methionine, and threonine) region is indicated. This is a critical part of the “inactivation particle” (inactivation gate), and substitution of aminoacids in this region can disrupt the inactivation process of the channel. The “docking site” consists of multiple regions that include the cytoplasmic linker between S4-S5 in domains III and IV, and the cytoplasmic end of the S6 segment in domain IV (*). Depending on the subtype of β subunit considered, they can interact (covalently or non-covalently) with the α subunit (From Savio-Galimberti E, Gollob MH, Darbar D. Voltage-gated sodium channels: biophysics, pharmacology, and related channelopathies. Front Pharmacol. 2012 Jul 11;3:124. Doi:10.3389/fphar.2012.00124. eCollection 2012.