title: Interactions between ankyrin-G, Plakophilin-2, and Connexin43 at the cardiac intercalated disc.
abstract: BACKGROUND
  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.
  
  
  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.
authors: Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: Priscila Y
authors: PY
authors: Sato
authors: Wanda
authors: W
authors: Coombs
authors: Xianming
authors: X
authors: Lin
authors: Oxana
authors: O
authors: Nekrasova
authors: Kathleen J
authors: KJ
authors: Green
authors: Lori L
authors: LL
authors: Isom
authors: Steven M
authors: SM
authors: Taffet
authors: Mario
authors: M
authors: Delmar
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