Molecular Pathology of Sodium Channel Beta-Subunit Variants

Paweorn Angsutararux,Taylor L Voelker,Jonathan R Silva,Wandi Zhu

doi:10.3389/fphar.2021.761275

Paweorn Angsutararux, Taylor L Voelker + Show 2 more

Open Access

https://doi.org/10.3389/fphar.2021.761275

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Abstract

The voltage-gated Na+ channel regulates the initiation and propagation of the action potential in excitable cells. The major cardiac isoform NaV1.5, encoded by SCN5A, comprises a monomer with four homologous repeats (I-IV) that each contain a voltage sensing domain (VSD) and pore domain. In native myocytes, NaV1.5 forms a macromolecular complex with NaVβ subunits and other regulatory proteins within the myocyte membrane to maintain normal cardiac function. Disturbance of the NaV complex may manifest as deadly cardiac arrhythmias. Although SCN5A has long been identified as a gene associated with familial atrial fibrillation (AF) and Brugada Syndrome (BrS), other genetic contributors remain poorly understood. Emerging evidence suggests that mutations in the non-covalently interacting NaVβ1 and NaVβ3 are linked to both AF and BrS. Here, we investigated the molecular pathologies of 8 variants in NaVβ1 and NaVβ3. Our results reveal that NaVβ1 and NaVβ3 variants contribute to AF and BrS disease phenotypes by modulating both NaV1.5 expression and gating properties. Most AF-linked variants in the NaVβ1 subunit do not alter the gating kinetics of the sodium channel, but rather modify the channel expression. In contrast, AF-related NaVβ3 variants directly affect channel gating, altering voltage-dependent activation and the time course of recovery from inactivation via the modulation of VSD activation.

Highlights

Electrical excitation of cardiomyocytes, the cardiac action potential, is initiated and propagated from myocyte to myocyte by the rapid conduction of inward Na+ current through voltage-gated Na+ (NaV) channels
Its transmembrane segment appears to interact with the VSDIII, while its Ig domain docks onto the surface constituting the extracellular loop of IV S6 and III S1-S2 (Figure 1A)
We found that there was no modulatory effect from these atrial fibrillation (AF)-linked β3 variants on the channel availability curves in relative to WT β3 (Figures 3B–D, left)

Summary

Introduction

Electrical excitation of cardiomyocytes, the cardiac action potential, is initiated and propagated from myocyte to myocyte by the rapid conduction of inward Na+ current through voltage-gated Na+ (NaV) channels. Each repeat contains six transmembrane segments (S1–S6), with the voltage sensing domain (VSD) formed by S1–S4 and the channel pore that is cooperatively defined by S5 and S6. NaV channel dysfunction caused by inherited variants can result in conduction diseases and deadly cardiac arrhythmias including atrial fibrillation (AF), long-QT syndrome (LQT), and Brugada syndrome (BrS) (Wang et al, 1995; Chen et al, 1998; Schott et al, 1999; Tan et al, 2001; Olson et al, 2005; Ellinor et al, 2008). Some mutations that alter NaV channel gating properties and affect the duration of action potential are found to predispose patients to AF (Olson et al, 2005; Ellinor et al, 2008)

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