Voltage-gated sodium channels (NaVs) are membrane proteins responsible for the rapid upstroke of the action potential in excitable cells. There are nine human voltage-sensitive NaV1 isoforms that, in addition to their sequence differences, differ in tissue distribution and specific function. This review focuses on isoforms NaV1.4 and NaV1.5, which are primarily expressed in skeletal and cardiac muscle cells, respectively. The determination of the structures of several eukaryotic NaVs by single-particle cryo-electron microscopy (cryo-EM) has brought new perspective to the study of the channels. Alignment of the cryo-EM structure of the transmembrane channel pore with x-ray crystallographic structures of the cytoplasmic domains illustrates the complementary nature of the techniques and highlights the intricate cellular mechanisms that modulate these channels. Here, we review structural insights into the cytoplasmic C-terminal regulation of NaV1.4 and NaV1.5 with special attention to Ca2+ sensing by calmodulin, implications for disease, and putative channel dimerization.
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4 January 2021
Review|
December 11 2020
Structural basis of cytoplasmic NaV1.5 and NaV1.4 regulation
Sara Nathan,
Sara Nathan
1
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD
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Sandra B. Gabelli,
1
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD
2
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
3
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
Correspondence to Sandra B. Gabelli: gabelli@jhmi.edu
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Jesse B. Yoder,
Jesse B. Yoder
1
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD
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Lakshmi Srinivasan,
Lakshmi Srinivasan
1
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD
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Richard W. Aldrich,
Richard W. Aldrich
4
Department of Neuroscience, University of Texas at Austin, Austin, TX
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Gordon F. Tomaselli,
Gordon F. Tomaselli
5
Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
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Manu Ben-Johny,
Manu Ben-Johny
6
Department of Physiology and Cellular Biophysics, Columbia University, New York, NY
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L. Mario Amzel
1
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD
3
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
L. Mario Amzel: mamzel@jhmi.edu
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Sara Nathan
1
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD
Sandra B. Gabelli
1
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD
2
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
3
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
Jesse B. Yoder
1
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD
Lakshmi Srinivasan
1
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD
Richard W. Aldrich
4
Department of Neuroscience, University of Texas at Austin, Austin, TX
Gordon F. Tomaselli
5
Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
Manu Ben-Johny
6
Department of Physiology and Cellular Biophysics, Columbia University, New York, NY
L. Mario Amzel
1
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD
3
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
Correspondence to Sandra B. Gabelli: gabelli@jhmi.edu
L. Mario Amzel: mamzel@jhmi.edu
Received:
July 31 2020
Accepted:
November 06 2020
Online Issn: 1540-7748
Print Issn: 0022-1295
Funding:
National Heart, Lung, and Blood Institute
(HL128743)
National Institutes of Health
(NO AWARD)
© 2020 Nathan et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Gen Physiol (2021) 153 (1): e202012722.
Article history
Received:
July 31 2020
Accepted:
November 06 2020
Citation
Sara Nathan, Sandra B. Gabelli, Jesse B. Yoder, Lakshmi Srinivasan, Richard W. Aldrich, Gordon F. Tomaselli, Manu Ben-Johny, L. Mario Amzel; Structural basis of cytoplasmic NaV1.5 and NaV1.4 regulation. J Gen Physiol 4 January 2021; 153 (1): e202012722. doi: https://doi.org/10.1085/jgp.202012722
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