| First Author | Bouza AA | Year | 2021 |
| Journal | JCI Insight | Volume | 6 |
| Issue | 3 | PubMed ID | 33411695 |
| Mgi Jnum | J:308987 | Mgi Id | MGI:6753622 |
| Doi | 10.1172/jci.insight.141776 | Citation | Bouza AA, et al. (2021) Sodium channel beta1 subunits participate in regulated intramembrane proteolysis-excitation coupling. JCI Insight 6(3) |
| abstractText | Loss-of-function (LOF) variants in SCN1B, encoding voltage-gated sodium channel beta1 subunits, are linked to human diseases with high risk of sudden death, including developmental and epileptic encephalopathy and cardiac arrhythmia. beta1 Subunits modulate the cell-surface localization, gating, and kinetics of sodium channel pore-forming alpha 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 beta1 by BACE1 and gamma-secretase and show that beta1 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 beta1-ICD overexpression in heterologous cells but upregulated in Scn1b-null cardiac tissue, which lacks beta1-ICD signaling, suggesting that the beta1-ICD may normally function as a molecular brake on gene transcription in vivo. We propose that human disease variants resulting in SCN1B 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 beta1 subunits. |
