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 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.
Lim
Byung-Kwan
BK
Department of Medicine, University of California San Diego, Division of Cardiology, La Jolla, California 92093-0613, USA.
Xiong
Dingding
D
Dorner
Andrea
A
Youn
Tae-Jin
TJ
Yung
Aaron
A
Liu
Taylor I
TI
Gu
Yusu
Y
Dalton
Nancy D
ND
Wright
Adam T
AT
Evans
Sylvia M
SM
Chen
Ju
J
Peterson
Kirk L
KL
McCulloch
Andrew D
AD
Yajima
Toshitaka
T
Knowlton
Kirk U
KU
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
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D017630:Connexins; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus; C082920:connexin 45