Coxsackievirus and adenovirus receptor (CAR) mediates atrioventricular-node function and connexin 45 localization in the murine heart

The coxsackievirus and adenovirus receptor (CAR) is a transmembrane protein that belongs to the family of adhesion molecules. In the postnatal heart, it is localized predominantly at the intercalated disc, where its function is not known. Here, we demonstrate that a first degree or complete block of...

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Bibliographic Details
Published in:The Journal of clinical investigation 2008-08, Vol.118 (8), p.2758-2770
Main Authors: Lim, Byung-Kwan, Xiong, Dingding, Dorner, Andrea, Youn, Tae-Jin, Yung, Aaron, Liu, Taylor I, Gu, Yusu, Dalton, Nancy D, Wright, Adam T, Evans, Sylvia M, Chen, Ju, Peterson, Kirk L, McCulloch, Andrew D, Yajima, Toshitaka, Knowlton, Kirk U
Format: Article
Language:English
Subjects:
Adenoviruses
Animals
Atrioventricular Node - metabolism
Biomedical research
Cardiomyopathy
Connexins - metabolism
Connexins - ultrastructure
Control
Coxsackie and Adenovirus Receptor-Like Membrane Protein
Coxsackieviruses
Electrocardiography
Embryo, Mammalian
Fluorescent Antibody Technique, Direct
Genetic aspects
Health aspects
Heart
Heart Ventricles - ultrastructure
HeLa Cells
Humans
Localization
Membrane proteins
Mice
Mice, Knockout
Myocarditis
Myocardium - metabolism
Myocardium - ultrastructure
Physiological aspects
Proteins
Receptors, Virus - metabolism
Receptors, Virus - ultrastructure
Risk factors
Telemetry
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Summary:The coxsackievirus and adenovirus receptor (CAR) is a transmembrane protein that belongs to the family of adhesion molecules. In the postnatal heart, it is localized predominantly at the intercalated disc, where its function is not known. Here, we demonstrate that a first degree or complete block of atrioventricular (AV) conduction developed in the absence of CAR in the adult mouse heart and that prolongation of AV conduction occurred in the embryonic heart of the global CAR-KO mouse. In the cardiac-specific CAR-KO (CAR-cKO) mouse, we observed the loss of connexin 45 localization to the cell-cell junctions of the AV node but preservation of connexin 40 and 43 in contracting myocardial cells and connexin 30.2 in the AV node. There was also a marked decrease in beta-catenin and zonula occludens-1 (ZO-1) localization to the intercalated discs of CAR-cKO mouse hearts at 8 weeks before the mice developed cardiomyopathy at 21 weeks of age. We also found that CAR formed a complex with connexin 45 via its PSD-95/DigA/ZO-1-binding (PDZ-binding) motifs. We conclude that CAR expression is required for normal AV-node conduction and cardiac function. Furthermore, localization of connexin 45 at the AV-node cell-cell junction and of beta-catenin and ZO-1 at the ventricular intercalated disc are dependent on CAR.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI34777