Circulation Research. 2002;90:317-324
Published online before print January 3, 2002, doi: 10.1161/hh0302.104471
Published online before print January 3, 2002, doi: 10.1161/hh0302.104471
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© 2002 American Heart Association, Inc.
Cellular Biology |
Increased Association of ZO-1 With Connexin43 During Remodeling of Cardiac Gap Junctions
From the Departments of Cell Biology and Anatomy (R.J.B., R.G.G.), Medical University of South Carolina, Charleston, SC; and the Department of Developmental Biology and Anatomy (R.L.P.), University of South Carolina School of Medicine, Columbia, SC.
Correspondence to Dr Robert G. Gourdie, Depts of Cell Biology and Anatomy, MUSC, 173 Ashley Ave, Suite 601, Charleston, SC 29425. E-mail gourdier{at}musc.edu
The intercellular geometry of connexin43 (Cx43) gap junctional coupling is key to coordinated spread of electrical activation through the ventricle of the mammalian heart. A progressive redistribution of electrical and mechanical junctions into intercalated discs occurs during postnatal development. Breakdown of disc-localized pattern in the adult heart, to recapitulate immature distributions, is thought to be key to the genesis of conduction disturbance and arrhythmia. Recently, ZO-1 (a PDZ-MAGUK protein), has been suggested to have a role in generating coupling geometries between myocytes. We therefore investigated the codistribution of ZO-1 with Cx43 and N-cadherin in the adult rat ventricle using quantitative immunoconfocal and immunoelectron microscopy. These analyses indicated that, whereas ZO-1 and Cx43 codistribute within discs, only low to moderate point-by-point colocalization of Cx43 and ZO-1 is found within these domains compared with the relatively high level of colocalization between N-cadherin and ZO-1. By contrast, levels of association between Cx43 and ZO-1 increased rapidly and significantly (P<0.001) after partial or complete enzymatic dissociation of myocytes from intact ventricle—a treatment known to induce gap junction endocytosis. Coimmunoprecipitation using Cx43- and ZO-1-specific antibodies confirmed that significantly (P<0.03) increased ZO-1 is precipitated relative to Cx43 in freshly dissociated myocytes as compared with intact ventricle. On immunoblots, decreases in Cx43 relative mobility, consistent with increased phosphorylation, were observed following myocyte dissociation. The increased ZO-1-Cx43 association that occurs after remodeling of myocyte intercellular contacts indicates the possibility of unanticipated roles for ZO-1 in gap junction turnover during cardiac development and disease processes.
Key Words: heart • gap junction • connexin • PDZ • ZO-1
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