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Stabilization of Dsg2 binding enhances GJ function and ameliorates arrhythmia caused by PG deficiency
Author(s) -
Erber Bernd Markus,
Schinner Camilla,
Schlipp Angela,
Waschke Jens
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.59.10
Subject(s) - plakoglobin , cadherin , intercalated disc , desmoplakin , microbiology and biotechnology , connexin , chemistry , medicine , gap junction , signal transduction , biology , gene , biochemistry , catenin , wnt signaling pathway , intracellular , cell
Arrhythmogenic cardiomyopathy (AC) is a genetic disease of the cardiomyocyte intercalated disc which causes cardiac arrhythmia and sudden cardiac death. Mutations primarily affect desmosomal proteins including the cadherin‐type adhesion molecule desmoglein 2 (Dsg2) and the plaque protein plakoglobin (Pg), which are known to be required for mechanical cohesion of cardiomyocytes, and thereby impair gap junction (GJ)‐mediated propagation of excitation by unknown mechanisms. Therefore, therapy is symptomatic at present. We provide evidence that stabilization of Dsg2‐binding by a tandem peptide (TP) enhances GJ signal transduction in cardiomyocytes. TP was designed to cross‐link Dsg2 molecules separate from the hydrophobic binding pocket of the extracellular domain 1. TP stabilized Dsg2 interaction on the surface of living cardiomyocytes as revealed by atomic force microscopy (AFM) and rescued cardiomyocyte cohesion when either tryptophan was used to block the binding pocket or Dsg2 and Pg were depleted by siRNA. In parallel, disturbed localization of connexin 43 (Cx43) and impaired GJ‐mediated excitation propagation were also abolished by TP, partly via a mechanism involving PKC phosphorylation of Cx43. In hearts from a cardiomyocyte‐specific Pg‐deletion mouse model for AC, TP reduced arrhythmia immediately upon perfusion. These results indicate that stabilization of Dsg2 binding may represent a new approach to treat arrhythmia in AC. Support or Funding Information Förderung für Forschung und Lehre (FöFoLe)