The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation
- Virginia Polytechnic University, United States
- Imperial College London, United Kingdom
- Case Western Reserve University, United States
- University of Michigan Medical School, United States
Abstract
Computational modeling indicates that cardiac conduction may involve ephaptic coupling - intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that β1(SCN1B) - mediated adhesion scaffolds trans-activating NaV1.5 (SCN5A) channels within narrow (<30 nm) perinexal clefts adjacent to gap junctions (GJs), facilitating ephaptic coupling. Super-resolution imaging indicated preferential β1 localization at the perinexus, where it co-locates with NaV1.5. Smart patch clamp (SPC) indicated greater sodium current density (INa) at perinexi, relative to non-junctional sites. A novel, rationally designed peptide, βadp1, potently and selectively inhibited β1-mediated adhesion, in electric cell-substrate impedance sensing studies. βadp1 significantly widened perinexi in guinea pig ventricles, and selectively reduced perinexal INa, but not whole cell INa, in myocyte monolayers. In optical mapping studies, βadp1 precipitated arrhythmogenic conduction slowing. In summary, β1-mediated adhesion at the perinexus facilitates action potential propagation between cardiomyocytes, and may represent a novel target for anti-arrhythmic therapies.
Data availability
The raw data generated in this study is available via Dryad (doi:10.5061/dryad.10351qn). The raw STORM movies are available on request from the corresponding author due to their large size.
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Data from: The Adhesion Function of the Sodium Channel Beta Subunit (β1) Contributes to Cardiac Action Potential PropagationAvailable at Dryad Digital Repository under a CC0 Public Domain Dedication.
Article and author information
Author details
Rengasayee Veeraraghavan
Funding
National Heart, Lung, and Blood Institute (RO1 HL56728-15A2)
- Robert G Gourdie
American Heart Association (16SDG29870007)
- Rengasayee Veeraraghavan
National Heart, Lung, and Blood Institute (R01 HL102298-01A1)
- Steven Poelzing
National Institutes of Health (R01 HL102298-01A1)
- James Smyth
National Institutes of Health (R37NS076752)
- Lori L Isom
National Heart, Lung, and Blood Institute (RO1 HL HL141855-01)
- Robert G Gourdie
National Heart, Lung, and Blood Institute (RO1 HL HL141855-01)
- Steven Poelzing
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). All animal study protocols (15-130, 15-134, 12-140) were approved by the Institutional Animal Care and Use Committee at the Virginia Polytechnic University.
Reviewing Editor
- Robert S Kaas, Columbia University Medical Center, United States
Publication history
- Received: April 17, 2018
- Accepted: August 6, 2018
- Accepted Manuscript published: August 14, 2018 (version 1)
- Accepted Manuscript updated: August 16, 2018 (version 2)
- Version of Record published: September 4, 2018 (version 3)
- Version of Record updated: October 19, 2018 (version 4)
Copyright
© 2018, Veeraraghavan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation
eLife 7:e37610.
https://doi.org/10.7554/eLife.37610
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