Anchored-PKA regulates connexin-43 gap junction communication in the heart - 26/03/18
Résumé |
Introduction |
In the heart, β-adrenergic receptor (β-AR) stimulation activates protein kinase A (PKA) and increases electrical conduction velocity (dromotropy). This process is mediated by connexin 43 (Cx43) that forms gap junction (GJ) channels and thus ensures a proper propagation of the electrical impulse, essential for sequential and coordinated contractions of cardiomyocytes. Regardless of the causes, a chronic activation of the β-AR signaling cascade leads to heart failure and contributes to an aberrant Cx43 expression. This affects electrical conduction, induces arrhythmias and uncoordinated contractions. We have previously shown that in placental cells, PKA anchored to ezrin allows rapid and direct phosphorylation of Cx43, which enhances GJ communication.
Objective |
Considering the key role of Cx43 in the heart, we decided to investigate the putative presence of a PKA-ezrin-Cx43 complex in cardiac cells and to explore its functional role in cardiac physiology and pathophysiology.
Method and results |
By immunolocalization studies, we found ezrin together with Cx43 and PKA expressed at the intercalated discs of purified adult rat ventricular cardiomyocytes (ARVC) and at the plasma membrane of neonatal ventricular cardiomyocytes (NRVC). We provided evidence that specific PKA-inhibitor and displacement of PKA from A-kinase anchoring proteins decreased Cx43 phosphorylation in β-AR-stimulated NRVC. Furthermore, proximity ligation assays and co-immunoprecipitations revealed that ezrin forms a molecular complex that directs PKA in the vicinity of Cx43. Proximity that was diminished with PKA-anchoring disrupting peptide. Finally, gap FRAP (fluorescence recovery after photobleaching) experiments in PKA-anchoring disrupting peptide treated NRVC, presented a reduction of GJ communication upon chronic β-AR stimulation.
Conclusion |
These data suggest a role of PKA-ezrin-Cx43 complex in the regulation of GJ communication in the heart.
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Vol 10 - N° 2
P. 213 - avril 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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