| Autor: |
Bouza AA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Edokobi N; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Hodges SL; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Pinsky AM; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Offord J; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Piao L; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Zhao YT; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Lopatin AN; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Lopez-Santiago LF; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Isom LL; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.; Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan, USA. |
| Abstrakt: |
Loss-of-function (LOF) variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are linked to human diseases with high risk of sudden death, including developmental and epileptic encephalopathy and cardiac arrhythmia. β1 Subunits modulate the cell-surface localization, gating, and kinetics of sodium channel pore-forming α 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 β1 by BACE1 and γ-secretase and show that β1 subunits are substrates for sequential RIP by BACE1 and γ-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 β1-ICD overexpression in heterologous cells but upregulated in Scn1b-null cardiac tissue, which lacks β1-ICD signaling, suggesting that the β1-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 β1 subunits. |
