Molecular Pathology of Sodium Channel Beta-Subunit Variants

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.

Cardiac sodium channel complexes and arrhythmia: structural and functional roles of the β1 and β3 subunits

“…The discordant findings may reflect the different model systems and experimental conditions, but collectively suggest differing mechanisms of Na V 1.5 channel modulation, despite both localising to the signal peptide. More surprising is the discordance in electrophysiological effects of the L10P and R6K within the same study (Angsutararux et al, 2021). Classically, mutations in this region, if deleterious, are anticipated to disrupt the production and/or trafficking of the protein.…”

Sodium channel subpopulations with distinct biophysical properties and subcellular localization enhance cardiac conduction

“…We highlight that our computational study is agnostic as to the specific “source” for the different biophysical properties between the Na + channel subpopulations, which could arise due to differences in interacting and scaffolding proteins at the distinct subcellular locations 1,2,8,56 . We speculate that association with different β subunits, which have been shown to alter Nav1.5 biophysical properties 5,6 , in different subcellular locations could also contribute to distinct Na + subpopulations. Finally, there is increasing evidence for the presence of different Nav1.x isoforms in cardiac myocytes, 57,58 which could also result in subpopulations with distinct biophysical properties.…”

“…Different interacting proteins have been found to impact expression, trafficking, internalization, phosphorylation, and modulation of channel biophysical properties. Additionally, Nav1.5 is known to associate with potentially four different β subunits, which can also impact channel surface expression and biophysical properties, in addition to playing a role in cellular adhesion [4][5][6][7] .…”

Predicting functional effects of ion channel variants using new phenotypic machine learning methods

“…Our model predicts functional effect at the alpha subunit level, but does PLOS COMPUTATIONAL BIOLOGY not include data from auxiliary beta subunits (SCN1B-SCN3B) or other modulator proteins (e.g. FGF12) which may themselves affect channel expression levels, gating kinetics, or neuronal network activity [51][52][53]. The model is trained on data from whole-cell patch-clamp recordings of mammalian cells but includes no further information on experimental metadata.…”