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Régulation fonctionnelle de la connexine 43 cardiaque par l'ancrage de la PKA

Abstract : Catecholamines' stimulation of beta- adrenergic receptors (β-ARs) activates cAMP-Protein Kinase A (PKA) signaling pathway leading to dromotropic positive effect, i.e., increase in action potential (AP) conduction velocity. AP is spread by gap junction (GJ) localized at cardiomyocytes intercalated discs (ID) which are composed by connexin 43 (Cx43). They ensure anisotropic AP conduction and thereby synchronous and homogenous heart contraction. Cardiac Cx43 altered expression and/or localization are known to affect AP conduction and favors ventricular arrhythmias after myocardial infarction (MI). MI is a major public health problem characterized by an ischemic lesion leading to irreversible cardiomyocytes' death. Regarding the cause, β-ARs are chronically activated to maintain cardiac function after MI. Considering the key role of GJ and β-ARs signaling in AP conduction, we investigated Cx43 spatio-temporal regulation by PKA in physiological and pathophysiological (MI) conditions.Experiments in which PKA was specifically inhibited or displaced from its anchoring to A Kinase Anchoring Proteins (AKAPs) with peptides showed an anchored-PKA phosphorylates Cx43 and regulates intercellular communication in ventricular cardiomyocytes. High resolution microscopy and biochemical approaches allowed us to identify for the time in cardiomyocytes a proteic macrocomplex composed of Cx43, the AKAP : ezrin and PKA. Finally, we observed in an acute MI model of LAD during 7 days a decreased proximity between Cx43 and ezrin at ID associated with a decreased Cx43 phosphorylation and an increased susceptibility to ventricular arrhythmias. We identified for the first in heart Cx43 and intercellular communication regulated by an anchored-PKA. Interestingly, a Cx43-ezrin-PKA complex localized at ID is disrupted after MI which could partially explain could explain the decrease in Cx43 phosphorylation, GJ uncoupling and ventricular arrhythmias.
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Submitted on : Thursday, June 23, 2022 - 10:54:12 AM
Last modification on : Saturday, June 25, 2022 - 3:26:20 AM

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  • HAL Id : tel-03702562, version 1

Citation

Anne-Sophie Colombe. Régulation fonctionnelle de la connexine 43 cardiaque par l'ancrage de la PKA. Cardiologie et système cardiovasculaire. Université Paris-Saclay, 2022. Français. ⟨NNT : 2022UPASQ019⟩. ⟨tel-03702562⟩

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