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Phosphatase-resistant gap junctions inhibit pathological remodeling and prevent arrhythmias.

ABSTRACT: Posttranslational phosphorylation of connexin43 (Cx43) has been proposed as a key regulatory event in normal cardiac gap junction expression and pathological gap junction remodeling. Nonetheless, the role of Cx43 phosphorylation in the context of the intact organism is poorly understood.To establish whether specific Cx43 phosphorylation events influence gap junction expression and pathological remodeling.We generated Cx43 germline knock-in mice in which serines 325/328/330 were replaced with phosphomimetic glutamic acids (S3E) or nonphosphorylatable alanines (S3A). The S3E mice were resistant to acute and chronic pathological gap junction remodeling and displayed diminished susceptibility to the induction of ventricular arrhythmias. Conversely, the S3A mice showed deleterious effects on cardiac gap junction formation and function, developed electric remodeling, and were highly susceptible to inducible arrhythmias.These data demonstrate a mechanistic link between posttranslational phosphorylation of Cx43 and gap junction formation, remodeling, and arrhythmic susceptibility.

SUBMITTER: Remo BF

PROVIDER: S-EPMC3126103 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Phosphatase-resistant gap junctions inhibit pathological remodeling and prevent arrhythmias.

Remo Benjamin F BF Qu Jiaxiang J Volpicelli Frank M FM Giovannone Steven S Shin Daniel D Lader Joshua J Liu Fang-Yu FY Zhang Jie J Lent Danielle S DS Morley Gregory E GE Fishman Glenn I GI

Circulation research 20110428 12

<h4>Rationale</h4>Posttranslational phosphorylation of connexin43 (Cx43) has been proposed as a key regulatory event in normal cardiac gap junction expression and pathological gap junction remodeling. Nonetheless, the role of Cx43 phosphorylation in the context of the intact organism is poorly understood.<h4>Objective</h4>To establish whether specific Cx43 phosphorylation events influence gap junction expression and pathological remodeling.<h4>Methods and results</h4>We generated Cx43 germline k ...[more]

PMID: 21527737

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Project description:Direct intercellular communication mediated by gap junctions (GJs) is a hallmark of normal cell and tissue physiology. In addition, GJs significantly contribute to physical cell-cell adhesion. Clearly, these cellular functions require precise modulation. Typically, GJs represent arrays of hundreds to thousands of densely packed channels, each one assembled from two half-channels (connexons), that dock head-on in the extracellular space to form the channel arrays that link neighboring cells together. Interestingly, docked GJ channels cannot be separated into connexons under physiological conditions, posing potential challenges to GJ channel renewal and physical cell-cell separation. We described previously that cells continuously-and effectively after treatment with natural inflammatory mediators-internalize their GJs in an endo-/exocytosis process that utilizes clathrin-mediated endocytosis components, thus enabling these critical cellular functions. GJ internalization generates characteristic cytoplasmic double-membrane vesicles, described and termed earlier annular GJs (AGJs) or connexosomes. Here, using expression of the major fluorescent-tagged GJ protein, connexin 43 (Cx43-GFP/YFP/mApple) in HeLa cells, analysis of endogenously expressed Cx43, ultrastructural analyses, confocal colocalization microscopy, pharmacological and molecular biological RNAi approaches depleting cells of key-autophagic proteins, we provide compelling evidence that GJs, following internalization, are degraded by autophagy. The ubiquitin-binding protein p62/sequestosome 1 was identified in targeting internalized GJs to autophagic degradation. While previous studies identified proteasomal and endo-/lysosomal pathways in Cx43 and GJ degradation, our study provides novel molecular and mechanistic insights into an alternative GJ degradation pathway. Its recent link to health and disease lends additional importance to this GJ degradation mechanism and to autophagy in general.

Dataset Information

Phosphatase-resistant gap junctions inhibit pathological remodeling and prevent arrhythmias.

Publications

Phosphatase-resistant gap junctions inhibit pathological remodeling and prevent arrhythmias.

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