ResearchIn-Press PreviewCardiologyCell biology
Open Access | 10.1172/jci.insight.141776
1Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, United States of America
2Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
3Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
Find articles by Bouza, A. in: JCI | PubMed | Google Scholar
1Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, United States of America
2Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
3Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
Find articles by
Edokobi, N.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, United States of America
2Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
3Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
Find articles by
Hodges, S.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, United States of America
2Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
3Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
Find articles by
Pinsky, A.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, United States of America
2Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
3Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
Find articles by Offord, J. in: JCI | PubMed | Google Scholar
1Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, United States of America
2Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
3Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
Find articles by Piao, L. in: JCI | PubMed | Google Scholar
1Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, United States of America
2Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
3Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
Find articles by
Zhao, Y.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, United States of America
2Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
3Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
Find articles by Lopatin, A. in: JCI | PubMed | Google Scholar
1Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, United States of America
2Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
3Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
Find articles by Lopez-Santiago, L. in: JCI | PubMed | Google Scholar
1Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, United States of America
2Department of Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
3Molecular & Integrative Physiology, The University of Michigan Medical School, Ann Arbor, United States of America
Find articles by
Isom, L.
in:
JCI
|
PubMed
|
Google Scholar
|
Published January 7, 2021 - More info
Background: Loss-of-function variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are linked to human diseases with high risk of sudden death, including epileptic encephalopathy and cardiac arrhythmia. β1 subunits modulate the cell-surface localization, gating, and kinetics of sodium channel pore-forming a 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. Methods: We investigated regulated intramembrane proteolysis (RIP) of β1 by BACE1 and γ-secretase.Results: We 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-seq, we identified a subset of genes that are downregulated by β1-ICD overexpression in heterologous cells but upregulated in Scn1b null cardiac tissue which, by definition, lacks β1-ICD signaling, suggesting that the β1-ICD may normally function as a molecular brake on gene transcription in vivo. Conclusion: We propose that human disease variants resulting in SCN1B loss-of-function cause transcriptional dysregulation that contributes to altered excitability. These results provide important new insights into the mechanism of SCN1B-linked channelopathies, adding RIP-excitation coupling to the multi-functionality of sodium channel β1 subunits.