cAMP signalling in the vasculature: the role of Epac (exchange protein directly activated by cAMP)

Roberts, Owain; Dart, Caroline

doi:10.1042/bst20130253

Cited by 55 publications

(49 citation statements)

References 92 publications

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“…The newly-discovered target of cAMP, exchange proteins directly activated by cAMP (Epac), has been revealed to be a novel downstream mechanism for cAMP to govern signaling in the cardiovascular system and other tissues [11, 12]. Its primary function is to act as guanine nucleotide exchange factors (GEF) for Rap GTPases—which act as molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state [13].…”

Section: Introductionmentioning

confidence: 99%

Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA

Zhang

Zhao

et al. 2017

PLoS ONE

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Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac) as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 μM), or ESI-09 (20 μM), or CE3F4 (100 μM), all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0.3–3 μM); while concurrent administration of BFA and PKI (5 μM), a PKA inhibitor, almost completely blocked the relaxation effect of G-1. The Epac specific agonist, 8-CPT-2Me-cAMP (007, 1–100 μM), induced a concentration-dependent relaxation response. Furthermore, the activity of Ras-related protein 1 (Rap1) was up regulated by G-1 (1 μM) treatment of porcine coronary artery smooth muscle cells (CASMCs). Phosphorylation of vasodilator-stimulated phosphoprotein (p-VASP) was elevated by G-1 (1 μM) treatment, but not by 007 (50 μM); and the effect of G-1 on p-VASP was blocked by PKI, but not by ESI-09, an Epac antagonist. RhoA activity was similarly down regulated by G-1 and 007, whereas ESI-09 restored most of the reduced RhoA activity by G-1 treatment. Furthermore, G-1 decreased PGF2α-induced p-MYPT1, which was partially reversed with either ESI-09 or PKI; whereas, concurrent administration of ESI-09 and PKI totally prevented the inhibitory effect of G-1. The inhibitory effects of G-1 on p- MLC levels in CASMCs were mostly restored by either ESI-09 or PKI. These results demonstrate that activation of GPER induces coronary artery relaxation via concurrent inhibition of RhoA/Rho kinase by Epac/Rap1 and PKA. GPER could be a potential drug target for preventing and treating cardiovascular diseases.

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Section: Introductionmentioning

confidence: 99%

Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA

Zhang

Zhao

et al. 2017

PLoS ONE

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“…57 Various mechanisms that do not necessarily exclude the participation of PKA are involved in EPAC vasorelaxant effect. 56,58,59 EPAC mediates vasorelaxation by indirectly regulating the activity of Ca 2+ -sensitive and ATP-sensitive K + channels within the endothelium and on VSMCs ( Figure 5). [59][60][61] In addition, EPAC-induced arterial smooth muscle relaxation may be a consequence of the activation of endothelial nitric oxide synthase and the subsequent production of nitric oxide, a potent vasodilatator molecule in endothelial cells ( Figure 5).…”

Section: Regulation Of the Vascular Tonementioning

confidence: 99%

“…56,58,59 EPAC mediates vasorelaxation by indirectly regulating the activity of Ca 2+ -sensitive and ATP-sensitive K + channels within the endothelium and on VSMCs ( Figure 5). [59][60][61] In addition, EPAC-induced arterial smooth muscle relaxation may be a consequence of the activation of endothelial nitric oxide synthase and the subsequent production of nitric oxide, a potent vasodilatator molecule in endothelial cells ( Figure 5). 62 Of particular importance, activation of EPAC-Rap1 signaling lowers VSMC contractility via the inhibition of the small GTPase RhoA activity, a master regulator of VSMC contraction and the dephosphorylation of myosin light chain ( Figure 5).…”

Section: Regulation Of the Vascular Tonementioning

confidence: 99%

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

Lezoualc’h

Fazal

Laudette

et al. 2016

Circulation Research

147

143

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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...

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“…High concentrations of lactate will reach receptors both at the luminal and abluminal surface of the endothelial cells, because of the presence of MCT1 (Lauritzen et al, 2011) as well as GPR81 (Lauritzen et al, 2013a,b) at both sides of the endothelium. Normally as well as in disease, cAMP is perhaps the most potent signaling molecule to stabilize the endothelial barrier, and also regulates inflammation response and vascular tone (Roberts and Dart, 2014; Schlegel and Waschke, 2014). It acts on three classes of proteins: protein kinase A (PKA), cyclic-nucleotide-gated ion channels, and Epacs (exchange proteins directly activated by cAMP).…”

Section: Hypothesis Of a New Factor In CMmentioning

confidence: 99%

“…In addition, increased vascular tone (Roberts and Dart, 2014) may aggravate the hypoperfusion caused by clogging of microvessels by sequestered erythrocytes. The effects via GPR81, and possibly other lactate receptors (cf.…”

Section: Hypothesis Of a New Factor In CMmentioning

confidence: 99%

Lactate transport and receptor actions in cerebral malaria

et al. 2014

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Cerebral malaria (CM), caused by Plasmodium falciparum infection, is a prevalent neurological disorder in the tropics. Most of the patients are children, typically with intractable seizures and high mortality. Current treatment is unsatisfactory. Understanding the pathogenesis of CM is required in order to identify therapeutic targets. Here, we argue that cerebral energy metabolic defects are probable etiological factors in CM pathogenesis, because malaria parasites consume large amounts of glucose metabolized mostly to lactate. Monocarboxylate transporters (MCTs) mediate facilitated transfer, which serves to equalize lactate concentrations across cell membranes in the direction of the concentration gradient. The equalizing action of MCTs is the basis for lactate’s role as a volume transmitter of metabolic signals in the brain. Lactate binds to the lactate receptor GPR81, recently discovered on brain cells and cerebral blood vessels, causing inhibition of adenylyl cyclase. High levels of lactate delivered by the parasite at the vascular endothelium may damage the blood–brain barrier, disrupt lactate homeostasis in the brain, and imply MCTs and the lactate receptor as novel therapeutic targets in CM.

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cAMP signalling in the vasculature: the role of Epac (exchange protein directly activated by cAMP)

Cited by 55 publications

References 92 publications

Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA

Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA

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

Lactate transport and receptor actions in cerebral malaria

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