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, Mario Delmar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

162 Scopus citations

Abstract

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 Nav1.5 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.

Original languageEnglish (US)
Pages (from-to)193-201
Number of pages9
JournalCirculation research
Volume109
Issue number2
DOIs
StatePublished - Jul 8 2011

Keywords

  • Ankyrin-G
  • Connexin43
  • Plakophilin-2
  • desmosomes
  • gap junctions

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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