title: Coxsackievirus and adenovirus receptor (CAR) mediates atrioventricular-node function and connexin 45 localization in the murine heart.
abstract: 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.
authors.affiliation: Department of Medicine, University of California San Diego, Division of Cardiology, La Jolla, California 92093-0613, USA.
authors.forename: Byung-Kwan
authors.initials: BK
authors.lastname: Lim
authors.forename: Dingding
authors.initials: D
authors.lastname: Xiong
authors.forename: Andrea
authors.initials: A
authors.lastname: Dorner
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Youn
authors.forename: Aaron
authors.initials: A
authors.lastname: Yung
authors.forename: Taylor I
authors.initials: TI
authors.lastname: Liu
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.forename: Adam T
authors.initials: AT
authors.lastname: Wright
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Yajima
authors.forename: Kirk U
authors.initials: KU
authors.lastname: Knowlton
mesh_terms: D000818:Animals; D001283:Atrioventricular Node / Q000378:metabolism*; D017630:Connexins / Q000378:metabolism* / Q000648:ultrastructure; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004562:Electrocardiography; D004622:Embryo, Mammalian; D019085:Fluorescent Antibody Technique, Direct; D006367:HeLa Cells; D006321:Heart; D006352:Heart Ventricles / Q000648:ultrastructure; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D011991:Receptors, Virus / Q000378:metabolism* / Q000648:ultrastructure; D013686:Telemetry
chemical_list: C568771:CLMP protein, human; C568772:CLMP protein, mouse; D017630:Connexins; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus; C082920:connexin 45