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ResearchIn-Press PreviewCardiologyCell biology Open Access | 10.1172/jci.insight.141776

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

Alexandra A. Bouza,1 Nnamdi Edokobi,1 Samantha L. Hodges,1 Alexa M. Pinsky,1 James Offord,1 Lin Piao,2 Yan-Ting Zhao,1 Anatoli N. Lopatin,3 Luis F. Lopez-Santiago,1 and Lori L. Isom1

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

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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

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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

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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

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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

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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

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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

JCI Insight. https://doi.org/10.1172/jci.insight.141776.
Copyright © 2021, Bouza et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 7, 2021 - Version history
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Abstract

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.

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