| Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction. | |
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MedLine Citation:
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PMID: 19342602 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Lateralization of the ventricular gap junction protein connexin 43 (Cx43) occurs in epicardial border zone myocytes following myocardial infarction (MI) and is arrhythmogenic. Alterations in Cx43 protein partners have been hypothesized to play a role in lateralization although mechanisms by which this occurs are unknown. To examine potential mechanisms we did nuclear magnetic resonance, yeast 2-hybrid, and surface plasmon resonance studies and found that the SH3 domain of the tyrosine kinase c-Src binds to the Cx43 scaffolding protein zonula occludens-1 (ZO-1) with a higher affinity than does Cx43. This suggests c-Src outcompetes Cx43 for binding to ZO-1, thus acting as a chaperone for ZO-1 and causing unhooking from Cx43. To determine whether c-Src/ZO-1 interactions affect Cx43 lateralization within the epicardial border zone, we performed Western blot, immunoprecipitation, and immunolocalization for active c-Src (p-cSrc) post-MI using a canine model of coronary occlusion. We found that post-MI p-cSrc interacts with ZO-1 as Cx43 begins to decrease its interaction with ZO-1 and undergo initial loss of intercalated disk localization. This indicates that the molecular mechanisms by which Cx43 is lost from the intercalated disk following MI includes an interaction of p-cSrc with ZO-1 and subsequent loss of scaffolding of Cx43 leaving Cx43 free to diffuse in myocyte membranes from areas of high Cx43, as at the intercalated disk, to regions of lower Cx43 content, the lateral myocyte membrane. Therefore shifts in Cx43 protein partners may underlie, in part, arrhythmogenesis in the post-MI heart. |
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Authors:
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Fabien Kieken; Nancy Mutsaers; Elena Dolmatova; Kelly Virgil; Andrew L Wit; Admir Kellezi; Bethany J Hirst-Jensen; Heather S Duffy; Paul L Sorgen |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-04-02 |
Journal Detail:
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Title: Circulation research Volume: 104 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2009 May |
Date Detail:
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Created Date: 2009-05-08 Completed Date: 2009-05-28 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 1103-12 Citation Subset: IM |
Affiliation:
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Department of Cardiology, Center for Life Sciences 9-913, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, Boston, MA 02115, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Binding, Competitive Connexin 43 / chemistry, metabolism* Disease Models, Animal Dogs Gap Junctions / enzymology, metabolism*, pathology Magnetic Resonance Spectroscopy Membrane Proteins / metabolism* Models, Molecular Molecular Sequence Data Myocardial Infarction / enzymology, metabolism*, pathology Myocytes, Cardiac / enzymology, metabolism*, pathology PDZ Domains Pericardium / enzymology, metabolism*, pathology Phosphoproteins / metabolism* Phosphorylation Protein Binding Protein Conformation Protein Interaction Domains and Motifs Protein Interaction Mapping Protein Transport Proto-Oncogene Proteins pp60(c-src) / chemistry, metabolism* Surface Plasmon Resonance Two-Hybrid System Techniques src Homology Domains |
| Grant Support | |
ID/Acronym/Agency:
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R01 GM 072631/GM/NIGMS NIH HHS; R01 HL 083205/HL/NHLBI NIH HHS; R01 HL B066140/HL/NHLBI NIH HHS; R01 HL083205-04/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Connexin 43; 0/Membrane Proteins; 0/Phosphoproteins; 0/zonula occludens-1 protein; EC 2.7.10.2/Proto-Oncogene Proteins pp60(c-src) |
| Comments/Corrections | |
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