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  • Initial investigations in the heart uncovered


    Initial investigations in the heart uncovered Epac as a positive regulator of myocyte hypertrophy [8], [9]. Concomitantly, Epac has been shown to regulate cardiac Ca homeostasis [8], [10], [11], [12], [13]. Ca is an essential second messenger in the cardiac physiology because its rhythmic variations activate contraction in each heartbeat through the mechanism of excitation–contraction (EC) coupling. Recent data indicate that Epac actions upon hypertrophy development and Ca homeostasis may be inter-regulated. In fact, Ca is involved in other processes through Ca activated signaling proteins with known hypertrophic transducing activity, notably the so-called excitation–transcription (ET) coupling. It has been recently shown that Epac regulation of intracellular Ca activates Ca-dependent transcription factors, activators of the hypertrophic program, and thus participating to the ET coupling [14], [15]. For those reasons it is the purpose of this review to discuss the involvement of the cAMP-binding protein Epac in EC and ET coupling. We start by describing Epac proteins and finish by citing the known pathological implication of Epac in the heart. We apologize for those authors whose valuable work is not cited.
    Epac proteins Two isoforms of Epac exist, Epac1 and Epac2 which are coded by two distinct pitavastatin RAPGEF3 and RAPGEF4, respectively [16], [17]. Epac isoforms respond to physiologically relevant cAMP concentrations and can be activated by Gs protein–coupled receptor (GsPCRs) such as β-adrenergic receptors (β-ARs) in cardiac myocytes [7], [18]. The cAMP analog and Epac agonist, 8-pCPT does not discriminate between Epac1 and Epac2 [6]. Epac isoforms are multi-domain proteins that include an N-terminal regulatory region and a C-terminal catalytic guanine nucleotide exchange factor (GEF) region. The C-terminal catalytic region consists of a CDC25 homology domain responsible for GEF activity, a Ras exchange motif (REM), which stabilizes the CDC25 homology domain, and a Ras association (RA) domain [1]. Epac1 and Epac2 promote the exchange of GDP for GTP in the Ras-like GTPases Rap1 and Rap2 upon binding to cAMP [7]. The N-terminal regulatory region of Epac proteins contains two domains: a disheveled, Egl-10, pleckstrin (DEP) domain which is responsible for membrane association and a high-affinity cAMP conserved binding domain. Epac2 isoform has an additional cyclic nucleotide binding domain which has 20 fold lower affinity for cAMP than the conserved binding domain and is dispensable for cAMP-induced Rap activation [19]. In the absence of cAMP, the regulatory region containing the cAMP-binding domain directly interacts with the catalytic region and inhibits GEF activity. Binding of cAMP to Epac induces large conformational changes within the pitavastatin protein and releases the auto-inhibitory effect of the N-terminal region, leading to Rap activation [1]. Although expressed in almost all tissues, Epac proteins have different patterns of expression and are developmentally regulated [20]. Epac1 mRNA is widely expressed but particularly abundant in kidney and heart while Epac2 is predominant in the brain and adrenal gland [17].
    Epac modulator of intracellular calcium After the first evidences of Epac effects in intracellular Ca observed in pancreatic cells [21], [22], several studies have demonstrated that the activation of endogenous Epac is also able to regulate Ca handling in cardiomyocytes [8], [10], [11], [12], [13], [15], [23], [24]. Although there may be time, microdomain, and species differences in the published data, it is clear today that Epac modulates cardiac Ca handling. In order to simplify, we have arbitrarily divided below the known actions of Epac on different compartments of the cell, including the effects on the cytosolic Ca ([Ca]i) under the EC coupling subheading and the effects on intranuclear Ca ([Ca]n) under the ET coupling subheading, although cytosolic Ca also participates in ET coupling through calcineurin/NFAT pathway.