Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Abstract

C yclic adenosine 3′,5′-monophosphate (cAMP) is one of the most studied signaling molecules that plays a critical role in cellular responses to extracellular stimuli in the cardiovascular system. It controls a wide range of biological effects, including cell proliferation, differentiation, and apoptosis. 1 cAMP is produced from ATP by transmembrane adenylyl cyclase on activation of Gs-coupled G protein-coupled receptors. 2In addition, soluble adenylyl cyclase is a second intracellular source of cAMP and can be activated by divalent cations in various subcellular compartments.3 The intracellular level of cAMP depends not only on its production by adenylyl cyclase but also its degradation by a large family of cAMP phosphodiesterases (PDEs), which catalyze the hydrolysis of cAMP into 5′-AMP. 4 PDEs are key actors in limiting the spread of cAMP and seem critical for the formation of dynamic microdomains that confer specific response to various hormones. 4 Besides specialized membrane structures that may also limit cAMP diffusion, A-kinase anchoring proteins function to tether cAMP effectors and PDEs enzymes into defined cellular compartments and, therefore, maintain localized pools of cAMP to control the cellular actions of the second messenger. 5Until recently, the intracellular effects of cAMP were attributed to the activation of protein kinase A (PKA) and cyclic nucleotide-gated ion channels. In 1998, a family of novel cAMP effector proteins named exchange proteins directly activated by cAMP (EPACs) was discovered. 6,7 The EPAC protein family is composed of EPAC1 and EPAC2, which act as guanine-nucleotide exchange factors (GEFs) for the small G proteins, Rap1 and Rap2, and function in a PKA-independent manner. 6,7 On binding to cAMP, EPAC promotes the exchange of GDP for GTP, thereby inducing the activation of the small G protein Rap.8 In contrast, Rap-GTPase-activating proteins enhance the intrinsic GTP hydrolysis activity of Rap leading to GTPase inactivation. 9The cycling of Rap between its inactive and active states provides a mechanism to regulate the binding to effector proteins.The discovery of EPAC proteins has broken the dogma surrounding cAMP and PKA, and uncovered new perspectives for the understanding of cAMP signaling in the cardiovascular system. The functions of these cAMP-sensitive GEFs in various subcellular compartments and cellular contexts are currently being unraveled, but given the availability of EPAC-specific ligands and engineered mouse models, a large body of evidence indicates that EPAC proteins are involved in multiple biological actions of cAMP, such as cardiac hypertrophy and vascular inflammation. In this review, after a description of EPAC protein structures and mechanism of activation, we discuss recent advances in the discovery of novel pharmacological modulators of EPAC (Figure 1). We provide an overview of the roles of EPAC proteins, their signalosome and compartmentation in cardiovascular function and diseases. We also discuss the therapeutic potential of EPAC ligands in the t...

Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death

“…42 Although these findings seem contradictory, Epac signaling is spatially and temporally regulated by diverse anchoring mechanisms that control specific functions of this cAMP-sensitive guanine exchange factor by recruitment to distinct subcellular localizations. 37 We, therefore, speculate that cell type-specific signals contribute to differential effect of Epac on mitochondrial ROS production.…”

“…Indeed, Epac proteins exert their biological function in combination with scaffolding proteins, such as β-arrestin, cAMP phosphodiesterases that regulates the duration and intensity of cAMP signaling, and PKA. 36,37 Because various mitochondrial compartments contain these proteins that are able to sense or respond to cAMP and may have antagonistic outputs, 2 further studies are needed to identify the multimolecular complexes that affect cAMP-Epac1 signaling and Epac1 mitochondrial function in cardiomyocytes.…”

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

“…Interestingly, even with these controversial results over the hypertrophic signaling of EPAC, EPAC-null hearts appear to be protected against many stress-induced myopathies and arrhythmias (785,819). Extensive effort has been invested into the determination of the EPAC-mediated signaling mechanisms in cardiomyopathies, arrhythmias, and heart failure which has been meticulously reviewed recently by two independent groups (320,601). Rather than redundantly reviewing these functions of EPAC, we refer the reader to these excellent reviews, and will instead focus on more recently identified roles for EPACs in vascular disease progression.…”

Extracellular adenosine‐induced Rac1 activation in pulmonary endothelium: Molecular mechanisms and barrier‐protective role

“…Indeed, there is a growing body of evidence showing that Rac1 protects the EC barrier, at least in part, via an Epac1‐Rap1 mediated signaling pathway (Aslam et al, ; Baumer, Spindler, Werthmann, Bunemann, & Waschke, ; Birukova et al, ). Activation of Epac‐Rap1 by its agonists enhances EC barrier function, reduces the destructive effects of inflammatory mediators on EC permeability and promotes cell junction stability (Cullere et al, ; Kooistra et al, ; Lezoualc'h, Fazal, Laudette, & Conte, ). Rap1‐mediated Rac1 activation may involve Rho A inhibition through activation of ARAP3, Rap‐dependent RhoGAP (Jeon et al, ; Jeon, Kim, Lee, et al, ; Jeon, Kim, Morii, et al, ).…”