The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation

  1. Rengasayee Veeraraghavan  Is a corresponding author
  2. Gregory S Hoeker
  3. Anita Alvarez-Laviada
  4. Daniel Hoagland
  5. Xiaoping Wan
  6. D Ryan King
  7. Jose Sanchez-Alonso
  8. Chunling Chen
  9. Jane Jourdan
  10. Lori L Isom
  11. Isabelle Deschenes
  12. James Smyth
  13. Julia Gorelik
  14. Steven Poelzing
  15. Robert G Gourdie  Is a corresponding author
  1. Virginia Polytechnic University, United States
  2. Imperial College London, United Kingdom
  3. Case Western Reserve University, United States
  4. 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.

The following data sets were generated

Article and author information

Author details

  1. Rengasayee Veeraraghavan

    Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, United States
    For correspondence
    saiv@vt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8364-2222
  2. Gregory S Hoeker

    Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Anita Alvarez-Laviada

    Department of Myocardial Function, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Daniel Hoagland

    Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xiaoping Wan

    Department of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. D Ryan King

    Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jose Sanchez-Alonso

    Department of Myocardial Function, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Chunling Chen

    Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jane Jourdan

    Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Lori L Isom

    Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Isabelle Deschenes

    Department of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. James Smyth

    Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Julia Gorelik

    Department of Myocardial Function, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Steven Poelzing

    Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Robert G Gourdie

    Virginia Tech Carilion Research Institute, Virginia Polytechnic University, Roanoke, United States
    For correspondence
    gourdier@vtc.vt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6021-0796

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

  1. Robert S Kaas, Columbia University Medical Center, United States

Publication history

  1. Received: April 17, 2018
  2. Accepted: August 6, 2018
  3. Accepted Manuscript published: August 14, 2018 (version 1)
  4. Accepted Manuscript updated: August 16, 2018 (version 2)
  5. Version of Record published: September 4, 2018 (version 3)
  6. 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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  1. Rengasayee Veeraraghavan
  2. Gregory S Hoeker
  3. Anita Alvarez-Laviada
  4. Daniel Hoagland
  5. Xiaoping Wan
  6. D Ryan King
  7. Jose Sanchez-Alonso
  8. Chunling Chen
  9. Jane Jourdan
  10. Lori L Isom
  11. Isabelle Deschenes
  12. James Smyth
  13. Julia Gorelik
  14. Steven Poelzing
  15. Robert G Gourdie
(2018)
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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