Voltage-gated sodium (Nav) channels produce the upstroke of action potentials in excitable tissues throughout the body. The gating of these channels is determined by the asynchronous movements of four voltage-sensing domains (VSDs). Past studies on the skeletal muscle Nav1.4 channel have indicated that VSD-I, -II, and -III are sufficient for pore opening, whereas VSD-IV movement is sufficient for channel inactivation. Here, we studied the cardiac sodium channel, Nav1.5, using charge-neutralizing mutations and voltage-clamp fluorometry. Our results reveal that both VSD-III and -IV are necessary for Nav1.5 inactivation, and that steady-state inactivation can be modulated by all VSDs. We also demonstrate that channel activation is partially determined by VSD-IV movement. Kinetic modeling suggests that these observations can be explained from the cardiac channel’s propensity to enter closed-state inactivation (CSI), which is significantly higher than that of other Nav channels. We show that skeletal muscle Nav1.4, cardiac Nav1.5, and neuronal Nav1.6 all have different propensities for CSI and postulate that these differences produce isoform-dependent roles for the four VSDs.
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May 25 2022
Closed-state inactivation of cardiac, skeletal, and neuronal sodium channels is isoform specific
Niklas Brake
,
1
Quantitative Life Sciences PhD Program, McGill University, Montreal, Quebec, Canada
2
Department of Physiology, McGill University, Montreal, Quebec, Canada
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Adamo S. Mancino
,
3
Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
4
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
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Yuhao Yan,
Yuhao Yan
3
Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
4
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
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Takushi Shimomura
,
Takushi Shimomura
5
Division of Biophysics and Neurobiology, National Institute for Physiological Sciences, Okazaki, Japan
6
Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Hayama, Japan
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Yoshihiro Kubo
,
Yoshihiro Kubo
5
Division of Biophysics and Neurobiology, National Institute for Physiological Sciences, Okazaki, Japan
6
Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Hayama, Japan
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Anmar Khadra
,
2
Department of Physiology, McGill University, Montreal, Quebec, Canada
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Derek Bowie
4
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
Correspondence to Derek Bowie: derek.bowie@mcgill.ca
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1
Quantitative Life Sciences PhD Program, McGill University, Montreal, Quebec, Canada
2
Department of Physiology, McGill University, Montreal, Quebec, Canada
3
Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
4
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
Yuhao Yan
3
Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
4
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
Takushi Shimomura
5
Division of Biophysics and Neurobiology, National Institute for Physiological Sciences, Okazaki, Japan
6
Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Hayama, Japan
Yoshihiro Kubo
5
Division of Biophysics and Neurobiology, National Institute for Physiological Sciences, Okazaki, Japan
6
Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Hayama, Japan
4
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
Correspondence to Derek Bowie: derek.bowie@mcgill.ca
*
N. Brake and A.S. Mancino contributed equally to this paper.
**
A. Khadra and D. Bowie are senior authors.
Received:
March 16 2021
Revision Received:
May 09 2022
Accepted:
May 12 2022
Online Issn: 1540-7748
Print Issn: 0022-1295
Funding
Funder(s):
Canadian Institutes of Health Research
- Award Id(s): MOP-342247
Funder(s):
Natural Sciences and Engineering Council of Canada
Funder(s):
Japan Society for the Promotion of Science London
- Award Id(s): 17H04021,20H03424
© 2022 Brake et al.
2022
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 (2022) 154 (7): e202112921.
Article history
Received:
March 16 2021
Revision Received:
May 09 2022
Accepted:
May 12 2022
Citation
Niklas Brake, Adamo S. Mancino, Yuhao Yan, Takushi Shimomura, Yoshihiro Kubo, Anmar Khadra, Derek Bowie; Closed-state inactivation of cardiac, skeletal, and neuronal sodium channels is isoform specific. J Gen Physiol 4 July 2022; 154 (7): e202112921. doi: https://doi.org/10.1085/jgp.202112921
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