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_V1.5, 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_V1.5 forms a macromolecular complex with Na_Vβ 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_Vβ1 and Na_Vβ3 are linked to both AF and BrS. Here, we investigated the molecular pathologies of 8 variants in Na_Vβ1 and Na_Vβ3. Our results reveal that Na_Vβ1 and Na_Vβ3 variants contribute to AF and BrS disease phenotypes by modulating both Na_V1.5 expression and gating properties. Most AF-linked variants in the Na_Vβ1 subunit do not alter the gating kinetics of the sodium channel, but rather modify the channel expression. In contrast, AF-related Na_Vβ3 variants directly affect channel gating, altering voltage-dependent activation and the time course of recovery from inactivation via the modulation of VSD activation.