The cAMP-responsive Rap1 Guanine Nucleotide Exchange Factor, Epac, Induces Smooth Muscle Relaxation by Down-regulation of RhoA Activity

Zieba, Bartosz J.; Artamonov, Mykhaylo V.; Jin, Li; Momotani, Ko; Ho, Ruoya; Franke, Aaron S.; Neppl, Ronald L.; Stevenson, Andrá S.; Khromov, Alexander S.; Chrzanowska‐Wodnicka, Magdalena; Somlyo, Avril V.

doi:10.1074/jbc.m110.205062

Cited by 89 publications

(102 citation statements)

References 66 publications

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“…Initial evidence for a role of EPAC, in particular EPAC1 in the regulation of vasorelaxation came from the observation that the EPAC agonist, 8-CPT and derived compounds directly relaxes several types of vascular smooth muscle preparations, for example cell preparation from rat aorta and pulmonary artery precontracted with endothelin. 55,56 Consistent with this finding, 8-CPT-induced relaxation is decreased in mouse vessels lacking a direct target of EPAC, Rap1B. 57 Of particular importance, Rap1B knockout mice develop hypertension, in part, via functional changes to VSMC and this indicates an essential role of Rap1 and possibly EPAC in maintaining normal vascular physiology.…”

Section: Regulation Of the Vascular Tonesupporting

confidence: 62%

“…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). 55,56 Conversely, in microvascular smooth muscle cells EPAC stimulates RhoA activity to increase the expression of functional α2C-ARs that mediate constriction of small blood vessels. 63 Altogether, these observations indicate that depending on the vascular bed, EPAC may induce vasorelaxation or vasoconstriction.…”

Section: Regulation Of the Vascular Tonementioning

confidence: 99%

“…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%

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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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Section: Regulation Of the Vascular Tonesupporting

confidence: 62%

Section: Regulation Of the Vascular Tonementioning

confidence: 99%

Section: Regulation Of the Vascular Tonementioning

confidence: 99%

See 1 more Smart Citation

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

Lezoualc’h

Fazal

Laudette

et al. 2016

Circulation Research

147

143

View full text Add to dashboard Cite

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“…A recent study reported the existence of a cross-talk between Rap1 and RhoA signaling pathways in vascular smooth muscle. Activation of Rap1 causes relaxation by decreasing the Ca 2ϩ sensitization of force in smooth muscle through downregulation of RhoA activity (588). Rap1 activation is triggered by the exchange factor Epac, activated by the rise in cAMP induced by the stimulation of vasorelaxing receptors such as ␤-adrenergic or prostglandine I 2 receptors.…”

Section: Ras Locus (H-ras-v12) (427) In Contrast H-rasmentioning

confidence: 99%

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Loirand

Sauzeau

Pacaud

2013

Physiological Reviews

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Small G proteins exist in eukaryotes from yeast to human and constitute the Ras superfamily comprising more than 100 members. This superfamily is structurally classified into five families: the Ras, Rho, Rab, Arf, and Ran families that control a wide variety of cell and biological functions through highly coordinated regulation processes. Increasing evidence has accumulated to identify small G proteins and their regulators as key players of the cardiovascular physiology that control a large panel of cardiac (heart rhythm, contraction, hypertrophy) and vascular functions (angiogenesis, vascular permeability, vasoconstriction). Indeed, basal Ras protein activity is required for homeostatic functions in physiological conditions, but sustained overactivation of Ras proteins or spatiotemporal dysregulation of Ras signaling pathways has pathological consequences in the cardiovascular system. The primary object of this review is to provide a comprehensive overview of the current progress in our understanding of the role of small G proteins and their regulators in cardiovascular physiology and pathologies.

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“…Surprisingly, the antispasmogenic activity of glucagon on carbachol-evoked contraction was unapparent after removal of the tracheal epithelium, clearly showing the crucial role of epithelial cells in this protective effect. This result was unexpected, once the elevation of intracellular cAMP levels leads to a relaxation of ASM (Zieba et al 2011, Billington et al 2013. To better explain this finding, we evaluated the expression of GcgR on both tracheal and lung tissue in mice from the A/J strain.…”

Section: Discussionmentioning

confidence: 99%

Glucagon induces airway smooth muscle relaxation by nitric oxide and prostaglandin E2

Insuela¹,

Daleprane²,

Coelho³

et al. 2015

Journal of Endocrinology

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Glucagon is a hyperglycemic pancreatic hormone that has been shown to provide a beneficial effect against asthmatic bronchospasm. We investigated the role of this hormone on airway smooth muscle contraction and lung inflammation using both in vitro and in vivo approaches. The action of glucagon on mouse cholinergic tracheal contraction was studied in a conventional organ bath system, and its effect on airway obstruction was also investigated using the whole-body pletysmographic technique in mice. We also tested the effect of glucagon on lipopolysaccharide (LPS)-induced airway hyperreactivity (AHR) and inflammation. The expression of glucagon receptor (GcgR), CREB, phospho-CREB, nitric oxide synthase (NOS)-3, pNOS-3 and cyclooxygenase (COX)-1 was evaluated by western blot, while prostaglandin E 2 (PGE 2 ) and tumour necrosis factor-a were quantified by enzyme-linked immunoassay and ELISA respectively. Glucagon partially inhibited carbacholinduced tracheal contraction in a mechanism clearly sensitive to des-His1-[Glu9]-glucagon amide, a GcgR antagonist. Remarkably, GcgR was more expressed in the lung and trachea with intact epithelium than in the epithelium-denuded trachea. In addition, the glucagon-mediated impairment of carbachol-induced contraction was prevented by either removing epithelial cells or blocking NOS (L-NAME), COX (indomethacin) or COX-1 (SC-560). In contrast, inhibitors of either heme oxygenase or COX-2 were inactive. Intranasal instillation of glucagon inhibited methacholine-induced airway obstruction by a mechanism sensitive to pretreatment with L-NAME, indomethacin and SC-560. Glucagon induced CREB and NOS-3 phosphorylation and increased PGE 2 levels in the lung tissue without altering COX-1 expression. Glucagon also inhibited LPS-induced AHR and bronchoalveolar inflammation. These findings suggest that glucagon possesses airway-relaxing properties that are mediated by epithelium-NOS-3-NO-and COX-1-PGE 2 -dependent mechanisms.

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The cAMP-responsive Rap1 Guanine Nucleotide Exchange Factor, Epac, Induces Smooth Muscle Relaxation by Down-regulation of RhoA Activity

Cited by 89 publications

References 66 publications

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

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

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Glucagon induces airway smooth muscle relaxation by nitric oxide and prostaglandin E2

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