Anchored-PKA regulates connexin 43 gap junctions communication in the heart

Abstract

In cardiomyocytes, connexin-43 (Cx43) forms gap junction (GJ) channels at the intercalated discs (ID) of cardiomyocytes and ensures electrical impulse propagation. This is essential for sequential and coordinated cardiac contractions. In physiological stress, β-adrenergic receptor (β-AR) stimulation activates protein kinase A (PKA), which increases electrical conduction velocity. In pathological condition of myocardial infarction (MI), the β-AR system is chronically activated. Furthermore, Cx43 is altered that affects GJ communication and electrical conduction leading to fatal arrhythmias. Considering the key role of Cx43 in electrical conduction, we investigated the functional regulation of GJ by PKA-anchored through A-kinase anchoring protein (AKAP) in cardiac physiology and pathophysiology, i.e. MI. Experiments in which PKA is inhibited or displaced from AKAPs point to a PKA-scaffold protein required for PKA-mediated regulation of Cx43 phosphorylation and GJ communication. By a variety of immunoprecipitation and immunolocalization experiments, we show that the AKAP named ezrin forms a molecular complex with PKA and Cx43 in rat hearts at the cellular and tissular levels. While PKA and ezrin expression levels remain constant, Cx43 show a significant reduction after a MI. Interestingly, immunolocalization studies highlight for a decrease in Cx43 vicinity with ezrin at the ID of ventricular cardiomyocytes. All of these suggest for a role of PKA-ezrin-Cx43 complex in the regulation of GJ communication in cardiac physiology and a deregulation of this complex could explain partly the altered electrical propagation observed after a MI.