Abstract
The second messenger 3′,5′-cyclic adenosine monophosphate (cAMP) is one of the most important signalling molecules in the heart as it regulates many physiological and pathophysiological processes. In addition to the classical protein kinase A (PKA) signalling route, the exchange proteins directly activated by cAMP (Epac) mediate the intracellular functions of cAMP and are now emerging as a new key cAMP effector in cardiac pathophysiology. In this review, we provide a perspective on recent advances in the discovery of new chemical entities targeting the Epac1 isoform and illustrate their use to study the Epac1 signalosome and functional characterisation in cardiac cells. We summarize the role of Epac1 in different subcompartments of the cardiomyocyte and discuss how cAMP–Epac1 specific signalling networks may contribute to the development of cardiac diseases. We also highlight ongoing work on the therapeutic potential of Epac1-selective small molecules for the treatment of cardiac disorders.
Highlights
INSERM UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, 31432 Toulouse, France; Université de Toulouse - Paul Sabatier, 31432 Toulouse, France
This finding is consistent with the localization of Epac2 at T tubules, the site of ryanodine receptors (RyR) expression in cardiomyocytes [55]. Contrasting to these studies, an Epac2 pharmacological inhibitor, ESI-05 increased early after-depolarization arrhythmia and the frequency of spontaneous Ca2+ sparks in adult rat ventricular myocytes, suggesting that Epac2 inhibition may be proarrhythmic [79]. These results reveal the complexity of Cyclic adenosine monophosphate (cAMP) signalling and demonstrate the necessity to perform additional in vivo studies to determine the functional profile of cardiac exchange proteins directly activated by cAMP (Epac) isoforms
Compelling evidence indicate that Epac1 forms discrete signalosomes with specific molecular partners inside distinct subcelullar compartments of cardiomyocytes
Summary
30 ,50 -Cyclic adenosine monophosphate (cAMP) is a universal second messenger that regulates a multitude of physiological and pathological processes. A (PKA), exchange proteins directly activated by cAMP proteins (Epac), cyclic nucleotide gated (CNG) ion channels, and Popeye domain-containing (POPDC) proteins [4,5,6,7] (Figure 1A). 3′,5′-Cyclic monophosphate (cAMP)-mediated signalling and exchange protein directly1.activated by adenosine cAMP (Epac) activation. ExchangeThe proteins directly activated by cAMP cyclic nucleotide and sculpt theAcAMP biological effects of cAMP areproteins ensured(Epac), by four downstream gated (CNG). CNBDGTP-loading induces a of Rap. conformational change that opens the catalytic CDC25-HD domain from autoinhibitory restraints and thereby permits GTP-loading of Rap. Classically, most biologic effects of cAMP in cardiomyoctes have been assigned to PKA, which promotes the acute of effects the β-adrenergic (β-AR)have on been cardiac contractility. We highlight the potential benefits of targeting Epac proteins for the treatment of cardiac diseases
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