Document Detail


Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction.
MedLine Citation:
PMID:  19342602     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-04-02
Journal Detail:
Title:  Circulation research     Volume:  104     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-05-08     Completed Date:  2009-05-28     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1103-12     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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
Zonula Occludens-1 Protein
src Homology Domains
Grant Support
ID/Acronym/Agency:
R01 GM 072631/GM/NIGMS NIH HHS; R01 HL 083205/HL/NHLBI NIH HHS; R01 HL B066140/HL/NHLBI NIH HHS; R01 HL083205/HL/NHLBI NIH HHS; R01 HL083205-04/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
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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