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Interactions Between Ankyrin-G, Plakophilin-2, and Connexin43 at the Cardiac Intercalated Disc
Journal article   Open access   Peer reviewed

Interactions Between Ankyrin-G, Plakophilin-2, and Connexin43 at the Cardiac Intercalated Disc

Priscila Y. Sato, Wanda Coombs, Xianming Lin, Oxana Nekrasova, Kathleen J. Green, Lori L. Isom, Steven M. Taffet and Mario Delmar
Circulation research, v 109(2), U160
08 Jul 2011
DOI: https://doi.org/10.1161/CIRCRESAHA.111.247023
PMID: 21617128
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.111.247023View
Published, Version of Record (VoR) Open
url
https://doi.org/10.1161/CIRCRESAHA.111.247023View
Published, Version of Record (VoR) Open

Abstract

Cardiac & Cardiovascular Systems Cardiovascular System & Cardiology Hematology Life Sciences & Biomedicine Peripheral Vascular Disease Science & Technology
Rationale: The early description of the intercalated disc defined 3 structures, all of them involved in cell-cell communication: desmosomes, gap junctions, and adherens junctions. Current evidence demonstrates that molecules not involved in providing a physical continuum between cells also populate the intercalated disc. Key among them is the voltage-gated sodium channel complex. An important component of this complex is the cytoskeletal adaptor protein Ankyrin-G (AnkG). Objective: To test the hypothesis that AnkG partners with desmosome and gap junction molecules and exerts a functional effect on intercellular communication in the heart. Methods and Results: We used a combination of microscopy, immunochemistry, patch-clamp, and optical mapping to assess the interactions between AnkG, Plakophilin-2, and Connexin43. Coimmunoprecipitation studies from rat heart lysate demonstrated associations between the 3 molecules. With the use of siRNA technology, we demonstrated that loss of AnkG expression caused significant changes in subcellular distribution and/or abundance of PKP2 and Connexin43 as well as a decrease in intercellular adhesion strength and electric coupling. Regulation of AnkG and of Na(v)1.5 by Plakophilin-2 was also demonstrated. Finally, optical mapping experiments in AnkG-silenced cells demonstrated a shift in the minimal frequency at which rate-dependence activation block was observed. Conclusions: These experiments support the hypothesis that AnkG is a key functional component of the intercalated disc at the intersection of 3 complexes often considered independent: the voltage-gated sodium channel, gap junctions, and the cardiac desmosome. Possible implications to the pathophysiology of inherited arrhythmias (such as arrhythmogenic right ventricular cardiomyopathy) are discussed. (Circ Res. 2011;109:193-201.)

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Collaboration types
Domestic collaboration
Web of Science research areas
Cardiac & Cardiovascular Systems
Hematology
Peripheral Vascular Disease
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