Document Detail


Phosphorylation of connexin43 on S279/282 may contribute to laminopathy-associated conduction defects.
MedLine Citation:
PMID:  23261543     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
An understanding of the molecular mechanism behind the arrhythmic phenotype associated with laminopathies has yet to emerge. A-type lamins have been shown to interact and sequester activated phospho-ERK1/2(pERK1/2) at the nucleus. The gap junction protein connexin43 (Cx43) can be phosphorylated by pERK1/2 on S279/282 (pS279/282), inhibiting intercellular communication. We hypothesized that without A-type lamins, pS279/282 Cx43 will increase due to inappropriate phosphorylation by pERK1/2, resulting in decreased gap junction function. We observed a 1.6-fold increase in pS279/282 Cx43 levels in Lmna(-/-) mouse embryonic fibroblasts (MEFs) compared to Lmna(+/+), and 1.8-fold more pERK1/2 co-precipitated from Lmna(-/-) MEFs with Cx43 antibodies. We found a 3-fold increase in the fraction of non-nuclear pERK1/2 and a concomitant 2-fold increase in the fraction of pS279/282 Cx43 in Lmna(-/-) MEFs by immunofluorescence. In an assay of gap junctional function, Lmna(-/-) MEFs transferred dye to 60% fewer partners compared to Lmna(+/+) controls. These results are mirrored in 5-6 week-old Lmna(-/-) mice compared to their Lmna(+/+) littermates as we detect increased pS279/282 Cx43 in gap junctions by immunofluorescence and 1.7-fold increased levels by immunoblot. We conclude that increased pS279/282 Cx43 in the Lmna(-/-) background results in decreased cell communication and may contribute to the arrhythmic pathology in vivo.
Authors:
Steven C Chen; Brian K Kennedy; Paul D Lampe
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-12-21
Journal Detail:
Title:  Experimental cell research     Volume:  319     ISSN:  1090-2422     ISO Abbreviation:  Exp. Cell Res.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-07     Completed Date:  2013-04-22     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  0373226     Medline TA:  Exp Cell Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  888-96     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Arrhythmias, Cardiac / metabolism,  pathology
Biological Transport
Cell Communication
Cell Nucleus / metabolism
Connexin 43 / genetics,  metabolism*
Cytoplasm / metabolism
Fibroblasts / metabolism
Fluorescent Antibody Technique
Gap Junctions / genetics,  metabolism
Heart Conduction System / metabolism,  pathology*
Lamin Type A / genetics,  metabolism*
MAP Kinase Signaling System
Mice
Phosphorylation
Protein Interaction Mapping
Serine / metabolism*
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
R01 AG024287/AG/NIA NIH HHS; R01 GM055632/GM/NIGMS NIH HHS; R01AG024287/AG/NIA NIH HHS; R01GM55632/GM/NIGMS NIH HHS; T32HL007312/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Connexin 43; 0/Lamin Type A; 452VLY9402/Serine
Comments/Corrections

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