Molecular Pathology of Sodium Channel Beta-Subunit Variants

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.