Sodium Channel Beta 1 Subunits Participate In Regulated Intramembrane Proteolysis-Excitation Coupling

Loss-of-function (LOF) variants in SCN1B, encoding voltage-gated sodium channel beta 1 subunits, are linked to human diseases with high risk of sudden death, including developmental and epileptic encephalopathy and cardiac arrhythmia. beta 1 Subunits modulate the cell-surface localization, gating, and kinetics of sodium channel pore-forming ix subunits. They also participate in cell-cell and cell-matrix adhesion, resulting in intracellular signal transduction, promotion of cell migration, calcium handling, and regulation of cell morphology. Here, we investigated regulated intramembrane proteolysis (RIP) of beta 1 by BACE1 and gamma-secretase and show that beta 1 subunits are substrates for sequential RIP by BACE1 and gamma-secretase, resulting in the generation of a soluble intracellular domain (ICD) that is translocated to the nucleus. Using RNA sequencing, we identified a subset of genes that are downregulated by beta 1-ICD overexpression in heterologous cells but unregulated in Scn1b- null cardiac tissue, which lacks beta 1-ICD signaling, suggesting that the beta 1-ICD may normally function as a molecular brake on gene transcription in vivo, We propose that human disease variants resulting in SCIV1B LOF cause transcriptional dysregulation that contributes to altered excitability. Moreover, these results provide important insights into the mechanism of SCN1B-linked channelopathies, adding RIP-excitation coupling to the multifunctionality of sodium channel beta 1 subunits.