Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling

Cell biology Cardiology Gene Expression Mice 03 medical and health sciences Cricetulus Loss of Function Mutation Animals Aspartic Acid Endopeptidases Humans Myocytes, Cardiac Cells, Cultured Excitation Contraction Coupling Mice, Knockout 0303 health sciences Cell Membrane R Voltage-Gated Sodium Channel beta-1 Subunit 16. Peace & justice 3. Good health HEK293 Cells Proteolysis Medicine RNA Splicing Factors Amyloid Precursor Protein Secretases Research Article Signal Transduction
DOI: 10.1172/jci.insight.141776 Publication Date: 2021-01-07T17:05:34Z
ABSTRACT
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 cardiac arrhythmia. Subunits modulate the cell-surface localization, gating, kinetics pore-forming α subunits. They also participate cell-cell cell-matrix adhesion, resulting intracellular signal transduction, promotion cell migration, calcium handling, regulation morphology. Here, we investigated regulated intramembrane proteolysis (RIP) by BACE1 γ-secretase show that subunits substrates for sequential RIP γ-secretase, generation a soluble domain (ICD) is translocated nucleus. Using RNA sequencing, identified subset genes downregulated β1-ICD overexpression heterologous cells but upregulated Scn1b-null tissue, which lacks signaling, suggesting may normally function as molecular brake on gene transcription vivo. We propose disease SCN1B LOF cause transcriptional dysregulation contributes altered excitability. Moreover, these results provide important insights into mechanism SCN1B-linked channelopathies, adding RIP-excitation coupling multifunctionality
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