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Interactions between ankyrin-G, Plakophilin-2, and Connexin43 at the cardiac intercalated disc.

Authors: Sato, PY  Coombs, W  Lin, X  Nekrasova, O  Green, KJ  Isom, LL  Taffet, SM  Delmar, M 
Citation: Sato PY, etal., Circ Res. 2011 Jul 8;109(2):193-201. Epub 2011 May 26.
Pubmed: (View Article at PubMed) PMID:21617128
DOI: Full-text: DOI:10.1161/CIRCRESAHA.111.247023

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.

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CRRD Object Information
CRRD ID: 6767286
Created: 2012-07-05
Species: All species
Last Modified: 2012-07-05
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.