The Epac1 Protein: Pharmacological Modulators, Cardiac Signalosome and Pathophysiology

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.

Keywords: 3′,5′-cyclic adenosine monophosphate (cAMP); cardiac disease; compartmentalization; exchange protein directly activated by cAMP 1 (Epac); small molecules.

Figure 1

3′,5′-Cyclic adenosine monophosphate (cAMP)-mediated signalling and exchange protein directly activated by cAMP (Epac)1 activation. (A) cAMP effectors in cardiac myocytes. Intracellular pool of cAMP is generated from ATP by two classes of adenylyl cyclases (AC): the membrane-bound AC and soluble AC (sAC). While membrane-bound AC is activated in response to Gαs-coupled G protein–coupled receptors (GPCRs) stimulation, sAC is directly activated by Ca²⁺ and bicarbonate. Phosphodiesterases (PDE), that hydrolyse cAMP to 5′-AMP, limit the local concentration of cAMP and sculpt the cAMP gradient. The biological effects of cAMP are ensured by four downstream effectors: protein kinase A (PKA), exchange proteins directly activated by cAMP proteins (Epac), cyclic nucleotide gated (CNG) ion channels, and Popeye domain-containing (POPDC) proteins. (B) Mechanism of Epac1 activation. The catalytic region of Epac1 contains the cell division cycle 25 homology domain (CDC25-HD), Ras-association (RA) domain and Ras-exchange motif (REM) domain. The Epac1 regulatory region includes the cyclic-nucleotide-binding domain (CNBD) and Dishevelled, Egl-10, Pleckstrin domain (DEP). Binding of cAMP to the CNBD induces a conformational change that opens the catalytic CDC25-HD domain from autoinhibitory restraints and thereby permits GTP-loading of Rap.

Figure 2

Epac1 signalosome in cardiac stress conditions. (A) Ischemia. In the context of cardiac ischemia, mitochondrial Epac1 is activated by the soluble adenylyl cyclases (sAC) and decreases reactive oxygen species (ROS) detoxification through isocitrate dehydrogenase 2 (IDH2) inhibition. In addition, Epac1 facilitates Ca²⁺ exchange from the endoplasmic reticulum (ER) to the mitochondrion by enhancing the formation of a Ca²⁺-handling macromolecular complex composed of voltage-dependent anion channel 1 (VDAC1), the chaperone glucose-regulated protein 75 (GRP75), and the inositol-1,4,5-trisphosphate (IP3) receptor 1 (IP3R1) between the ER and the mitochondrion interface. Epac1-induced Ca²⁺ overload and ROS accumulation promotes mitochondrial permeability transition pore (mPTP) opening and cardiomyocyte death. (B) Adrenergic stress. Under chronic β-adrenergic receptor (β-AR) stimulation, the β-arrestin/Epac1 complex is recruited at the plasma membrane and activates a Rap2/phospholipase C (PLC)ε pathway to induce 1,4,5-trisphosphate production. This signalling pathway converges to the nucleus to promote nuclear Ca²⁺ load, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) activation, histone deacetylase type 4 (HDAC4) nuclear export and eventually activation of the prohypertrophic transcription factor, myocyte enhancer factor 2 (MEF2). In addition, Epac1 induces G-protein receptor kinase 5 (GRK5) nuclear import and histone deacetylase type 5 (HDAC5) nuclear export to promote MEF2 activity. Yet, Epac1 prohypertrophic signalling includes the phosphatase calcineurin (CaN) and nuclear factor of activated T cells (NFAT). cAMP synthesized at the Golgi by intracellular β-AR may also stimulate the prohypertrophic Epac1/PLCε/A-kinase anchoring protein (mAKAP) signalling at the nuclear membrane of cardiomyocytes. (C) Arrhythmia. Epac1 activation contributes to cardiac rhythm disorders by increasing the expression level of pro-arrhythmic channels (transient receptor potential canonical (TRPC) 3/4 and potassium voltage-gated channel (KCN)). Epac1 also promotes spontaneous diastolic Ca²⁺ leak via CaMKII-dependent ryanodine receptors (RyR) hyperphosphorylation.