Ankyrin-G mediates targeting of both Na+ and KATP channels to the rat cardiac intercalated disc

  1. Hua-Qian Yang
  2. Marta Pérez-Hernández
  3. Jose Sanchez-Alonso
  4. Andriy Shevchuk
  5. Julia Gorelik
  6. Eli Rothenberg
  7. Mario Delmar
  8. William A Coetzee  Is a corresponding author
  1. New York University School of Medicine, United States
  2. Imperial College London, United Kingdom

Abstract

We investigated targeting mechanisms of Na+ and KATP channels to the intercalated disk (ICD) of cardiomyocytes. Patch clamp and surface biotinylation data show reciprocal downregulation of each other's surface density. Mutagenesis of the Kir6.2 ankyrin binding site disrupts this functional coupling. Duplex patch clamping and Angle SICM recordings show that INa and IKATP functionally co-localize at the rat ICD, but not at the lateral membrane. Quantitative STORM imaging show that Na+ and KATP channels are localized close to each other and to AnkG, but not to AnkB, at the ICD. Peptides corresponding to Nav1.5 and Kir6.2 ankyrin binding sites dysregulate targeting of both Na+ and KATP channels to the ICD, but not to lateral membranes. Finally, a clinically relevant gene variant that disrupts KATP channel trafficking also regulates Na+ channel surface expression. The functional coupling between these two channels need to be considered when assessing clinical variants and therapeutics.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Hua-Qian Yang

    Department of Pediatrics, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Marta Pérez-Hernández

    Department of Medicine, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jose Sanchez-Alonso

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Andriy Shevchuk

    Department of Medicine, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Julia Gorelik

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1148-9158
  6. Eli Rothenberg

    Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1382-1380
  7. Mario Delmar

    Department of Medicine, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. William A Coetzee

    Department of Pediatrics, New York University School of Medicine, New York, United States
    For correspondence
    william.coetzee@nyu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1522-8326

Funding

National Institutes of Health (HL126905)

  • William A Coetzee

National Institutes of Health (HL145911)

  • Mario Delmar

National Institutes of Health (HL126802)

  • Julia Gorelik

Leducq Foundation

  • Eli Rothenberg
  • Mario Delmar

Rafael del Pino Foundation

  • Marta Pérez-Hernández

Biotechnology and Biological Sciences Research Council (BB/M022080)

  • Andriy Shevchuk

British Heart Foundation (RG/17/13/33173)

  • Jose Sanchez-Alonso
  • Julia Gorelik

American Heart Association (17POST33370050)

  • Hua-Qian Yang

National Institutes of Health (HL146514)

  • William A Coetzee

National Institutes of Health (HL134328)

  • Mario Delmar

National Institutes of Health (HL136179)

  • Mario Delmar

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of New York University School of Medicine (protocol s17-00352).

Reviewing Editor

  1. Baron Chanda, University of Wisconsin-Madison, United States

Publication history

  1. Received: October 2, 2019
  2. Accepted: January 11, 2020
  3. Accepted Manuscript published: January 14, 2020 (version 1)
  4. Version of Record published: January 24, 2020 (version 2)

Copyright

© 2020, Yang 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. Hua-Qian Yang
  2. Marta Pérez-Hernández
  3. Jose Sanchez-Alonso
  4. Andriy Shevchuk
  5. Julia Gorelik
  6. Eli Rothenberg
  7. Mario Delmar
  8. William A Coetzee
(2020)
Ankyrin-G mediates targeting of both Na+ and KATP channels to the rat cardiac intercalated disc
eLife 9:e52373.
https://doi.org/10.7554/eLife.52373

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