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Title: Ca2+-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif

Abstract

Skeletal muscle voltage-gated Na+ channel (NaV1.4) activity is subject to calmodulin (CaM) mediated Ca2+-dependent inactivation; no such inactivation is observed in the cardiac Na+ channel (NaV1.5). Taken together, the crystal structures of the NaV1.4 C-terminal domain relevant complexes and thermodynamic binding data presented here provide a rationale for this isoform difference. A Ca2+-dependent CaM N-lobe binding site previously identified in NaV1.5 is not present in NaV1.4 allowing the N-lobe to signal other regions of the NaV1.4 channel. Consistent with this mechanism, removing this binding site in NaV1.5 unveils robust Ca2+-dependent inactivation in the previously insensitive isoform. These findings suggest that Ca2+-dependent inactivation is effected by CaM’s N-lobe binding outside the NaV C-terminal while CaM’s C-lobe remains bound to the NaV C-terminal. As the N-lobe binding motif of NaV1.5 is a mutational hotspot for inherited arrhythmias, the contributions of mutation-induced changes in CDI to arrhythmia generation is an intriguing possibility.

Authors:
 [1];  [2];  [3];  [1];  [1];  [4]; ORCiD logo [5];  [1]
  1. Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
  2. Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, 10032, USA
  3. Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
  4. Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
  5. Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); NIH National Institute of General Medical Sciences
OSTI Identifier:
1624148
Grant/Contract Number:  
SC0012704; HL128743; P41GM111244; KP1605010; KC0401040
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
Science & Technology - Other Topics

Citation Formats

Yoder, Jesse B., Ben-Johny, Manu, Farinelli, Federica, Srinivasan, Lakshmi, Shoemaker, Sophie R., Tomaselli, Gordon F., Gabelli, Sandra B., and Amzel, L. Mario. Ca2+-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif. United States: N. p., 2019. Web. doi:10.1038/s41467-019-09570-7.
Yoder, Jesse B., Ben-Johny, Manu, Farinelli, Federica, Srinivasan, Lakshmi, Shoemaker, Sophie R., Tomaselli, Gordon F., Gabelli, Sandra B., & Amzel, L. Mario. Ca2+-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif. United States. doi:10.1038/s41467-019-09570-7.
Yoder, Jesse B., Ben-Johny, Manu, Farinelli, Federica, Srinivasan, Lakshmi, Shoemaker, Sophie R., Tomaselli, Gordon F., Gabelli, Sandra B., and Amzel, L. Mario. Wed . "Ca2+-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif". United States. doi:10.1038/s41467-019-09570-7. https://www.osti.gov/servlets/purl/1624148.
@article{osti_1624148,
title = {Ca2+-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif},
author = {Yoder, Jesse B. and Ben-Johny, Manu and Farinelli, Federica and Srinivasan, Lakshmi and Shoemaker, Sophie R. and Tomaselli, Gordon F. and Gabelli, Sandra B. and Amzel, L. Mario},
abstractNote = {Skeletal muscle voltage-gated Na+ channel (NaV1.4) activity is subject to calmodulin (CaM) mediated Ca2+-dependent inactivation; no such inactivation is observed in the cardiac Na+ channel (NaV1.5). Taken together, the crystal structures of the NaV1.4 C-terminal domain relevant complexes and thermodynamic binding data presented here provide a rationale for this isoform difference. A Ca2+-dependent CaM N-lobe binding site previously identified in NaV1.5 is not present in NaV1.4 allowing the N-lobe to signal other regions of the NaV1.4 channel. Consistent with this mechanism, removing this binding site in NaV1.5 unveils robust Ca2+-dependent inactivation in the previously insensitive isoform. These findings suggest that Ca2+-dependent inactivation is effected by CaM’s N-lobe binding outside the NaV C-terminal while CaM’s C-lobe remains bound to the NaV C-terminal. As the N-lobe binding motif of NaV1.5 is a mutational hotspot for inherited arrhythmias, the contributions of mutation-induced changes in CDI to arrhythmia generation is an intriguing possibility.},
doi = {10.1038/s41467-019-09570-7},
journal = {Nature Communications},
issn = {2041-1723},
number = 1,
volume = 10,
place = {United States},
year = {2019},
month = {4}
}

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