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
AUTHORS (10)
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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CITATIONS (23)
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