Role of desmosomes in cardiac electrical function

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PROJECT SUMMARY Our long-term goal is to understand the relation between adhesion molecules and cardiac electrical function. We center on Plakophilin-2 (PKP2), a molecule classically defined as a component of the desmosome, though also known to cover functions beyond cell-cell adhesion. Mutations in PKP2 are recognized as the most common cause of familial arrhythmogenic right ventricular cardiomyopathy (ARVC) of known genetic origin. ARVC is characterized by fibrofatty infiltration, most commonly of right ventricular predominance, ventricular arrhythmias and sudden cardiac death in the young. RV predominance and the high incidence of life- threatening arrhythmias during the early stages of disease have puzzled investigators for years. The study of these features has been hampered by the lack of an animal model that reproduces the natural course of this condition. We have generated a cardiac-specific, tamoxifen-activated, PKP2 knockout murine line (PKP2- cKO). To our knowledge, this is the first animal model with an arrhythmogenic cardiomyopathy of right ventricular predominance that results from PKP2 dysfunction. Our aims are: 1: To characterize the arrhythmogenic phenotype following loss of PKP2 expression. Hypothesis: We propose that loss of PKP2 expression leads to a stage of arrhythmogenicity that precedes heart failure, characterized by asymmetric electrical remodeling of the ventricles. We further propose that such remodeling involves changes in electrical coupling and in sodium current properties, and that arrhythmias are triggered by dysregulation of Cai homeostasis. We postulate that this alteration is, in part, secondary to a) alterations in exon usage and b) changes in transcription of genes not previously linked to adhesion-related pathways and yet relevant to electrophysiology. 2: To characterize the nano-structural phenotype following loss of PKP2 expression. Hypothesis: We postulate that the recently described adhesion/excitability nodes (“mini-nodes of Ranvier”) at the ID act as points of convergence of two signaling platforms: One scaffolded by Ankyrin-G and the other, by PKP2. We further propose that loss of PKP2 expression leads to separation and eventual loss of the components of the adhesion/excitability node, including three key initiators of intracellular signaling cascades: CAMKII, PKCα and beta-catenin. We speculate that these changes are accompanied by asymmetrical (right vs left) changes in a) intercellular space dimensions and b) the anatomy of the dyad, thus contributing to the functional changes observed in the early-stage arrhythmogenic phenotype.