Molecular Pathology of Sodium Channel Beta-Subunit Variants
Paweorn Angsutararux, Wandi Zhu, Taylor L. Voelker, Jonathan R. Silva
Abstract
The voltage-gated Na + channel regulates the initiation and propagation of the action potential in excitable cells. The major cardiac isoform Na V 1.5, 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, Na V 1.5 forms a macromolecular complex with Na V β subunits and other regulatory proteins within the myocyte membrane to maintain normal cardiac function. Disturbance of the Na V 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 Na V β1 and Na V β3 are linked to both AF and BrS. Here, we investigated the molecular pathologies of 8 variants in Na V β1 and Na V β3. Our results reveal that Na V β1 and Na V β3 variants contribute to AF and BrS disease phenotypes by modulating both Na V 1.5 expression and gating properties. Most AF-linked variants in the Na V β1 subunit do not alter the gating kinetics of the sodium channel, but rather modify the channel expression. In contrast, AF-related Na V β3 variants directly affect channel gating, altering voltage-dependent activation and the time course of recovery from inactivation via the modulation of VSD activation.