Epac stimulation induces rapid increases in connexin43 phosphorylation and function without preconditioning effect

Duquesnes, Nicolas; Derangeon, Mickaël; Métrich, Mélanie; Lucas, Alexandre; Matéo, Philippe; Li, Lin; Morel, Éric; Lezoualc’h, Frank; Crozatier, Bertrand

doi:10.1007/s00424-010-0854-9

Cited by 29 publications

(21 citation statements)

References 45 publications

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“…Consistent with the results reported by others (Duquesnes et al, 2010) who used a similar model of I/R, perfusion of hearts with the Epac agonist CPT did not show a clear protective effect. Nonetheless, we found that perfusion of hearts with the mixture of the specific PKA activator 6‐Bnz and the Epac activator CPT resulted in relatively very high haemodynamic functional recovery (Figure 7A and Table 2), significantly reduced LDH release and infarct size during reperfusion (Figure 7B–C).…”

Section: Discussionsupporting

confidence: 92%

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

Khaliulin

Bond

James

et al. 2017

British J Pharmacology

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Background and PurposeMyocardial cAMP elevation confers cardioprotection against ischaemia/reperfusion (I/R) injury. cAMP activates two independent signalling pathways, PKA and Epac. This study investigated the cardiac effects of activating PKA and/or Epac and their involvement in cardioprotection against I/R.Experimental ApproachHearts from male rats were used either for determination of PKA and PKC activation or perfused in the Langendorff mode for either cardiomyocyte isolation or used to monitor functional activity at basal levels and after 30 min global ischaemia and 2 h reperfusion. Functional recovery and myocardial injury during reperfusion (LDH release and infarct size) were evaluated. Activation of PKA and/or Epac in perfused hearts was induced using cell permeable cAMP analogues in the presence or absence of inhibitors of PKA, Epac and PKC. H9C2 cells and cardiomyocytes were used to assess activation of Epac and effect on Ca2+ transients.Key ResultsSelective activation of either PKA or Epac was found to trigger a positive inotropic effect, which was considerably enhanced when both pathways were simultaneously activated. Only combined activation of PKA and Epac induced marked cardioprotection against I/R injury. This was accompanied by PKCε activation and repressed by inhibitors of PKA, Epac or PKC.Conclusion and ImplicationsSimultaneous activation of both PKA and Epac induces an additive inotropic effect and confers optimal and marked cardioprotection against I/R injury. The latter effect is mediated by PKCε activation. This work has introduced a new therapeutic approach and targets to protect the heart against cardiac insults.

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Section: Discussionsupporting

confidence: 92%

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

Khaliulin

Bond

James

et al. 2017

British J Pharmacology

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“…Cx43 has a high turnover rate with a half-life of ~1-2 h, this condition permits rapid adjustments of cell-cell communication with transcriptional regulation and degradation (18). Modulation of cAMP and its relevant signaling pathway Epac are reported to affect the level of Cx43 and its phosphorylation in the heart (19,20) and endothelial cells (21). However, the molecular nature of β2-AR stimulation and cAMP derivative induced Cx43 expression in astrocytoma cells remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Selective β2 adrenergic agonist increases Cx43 and miR-451 expression via cAMP-Epac

Mostafavi

Khaksarian

Joghataei

et al. 2014

Molecular Medicine Reports

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Abstract. It has been demonstrated that connexin 43 (Cx43) and microRNAs have significant roles in glioma. Cyclic adenosine monophosphate (cAMP) is suggested to be a regulator of connexins and microRNAs. However, it remains elusive whether cAMP and exchange protein directly activated by cAMP (Epac2), have a regulatory effect on Cx43 and microRNA-451 (miR-451) in astrocytoma cells. We treated 1321N1 astrocytoma cells with a selective β2 adrenergic agonist and a selective Epac activator with and without adenyl cyclase and protein kinase A inhibition. Cx43 and miR-451 expression were measured. Next, we evaluated the effect of miR-451 overexpression on Cx43 expression. Cell proliferation was measured using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results demonstrated that cAMPEpac2 increased Cx43 and miR-451 expression. However, the alteration of miR-451 expression required a higher dose of drugs. Overexpression of miR-451 had no significant effect on Cx43 expression. The MTT assay showed that cAMP-Epac stimulation and miR-451 overexpression had a synergic inhibitory effect on cell proliferation. These findings may expand our understanding of the molecular biology of glioma and provide new potential therapeutic targets.

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“…In particular, some studies reported that EPAC regulates the expression and localization of the main ventricular gap junction protein connexin 43 in a Rap1-and PKCε-dependent manner, thereby influencing the gating function of Gap junctions. 121,122 Considering the importance of connexin 43 in the regulation of electric cell-to-cell coupling and the pathogenesis of ventricular arrhythmias, 123 we can speculate that EPAC contributes to electric remodeling via alterations of gap junction formation.…”

Section: Epac and Cardiac Electric Remodelingmentioning

confidence: 99%

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

Lezoualc’h

Fazal

Laudette

et al. 2016

Circulation Research

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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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Epac stimulation induces rapid increases in connexin43 phosphorylation and function without preconditioning effect

Cited by 29 publications

References 45 publications

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

Selective β2 adrenergic agonist increases Cx43 and miR-451 expression via cAMP-Epac

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

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