Ankyrin-G mediates targeting of both Na+ and KATP channels to the rat cardiac intercalated disc
- New York University School of Medicine, United States
- 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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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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).
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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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
