Specific interactions between Epac1, β-arrestin2 and PDE4D5 regulate β-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling

Berthouze-Duquesnes, Magali; Lucas, Alexandre; Saulière, Aude; Sin, Yuan Yan; Laurent, Anne‐Coline; Galès, Céline; Baillie, George S.; Lezoualc’h, Frank

doi:10.1016/j.cellsig.2012.12.007

Cited by 52 publications

(52 citation statements)

References 50 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death

Fazal

Laudette

Paula-Gomes

et al. 2017

Circulation Research

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100

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Rationale: Although the second messenger cyclic AMP (cAMP) is physiologically beneficial in the heart, it largely contributes to cardiac disease progression when dysregulated. Current evidence suggests that cAMP is produced within mitochondria. However, mitochondrial cAMP signaling and its involvement in cardiac pathophysiology are far from being understood.Objective: To investigate the role of MitEpac1 (mitochondrial exchange protein directly activated by cAMP 1) in ischemia/reperfusion injury. Methods and Results:

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Section: Discussionmentioning

confidence: 99%

Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death

Fazal

Laudette

Paula-Gomes

et al. 2017

Circulation Research

Self Cite

100

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“…Coimmunoprecipitation and bioluminescence resonance energy transfer experiments showed that β1-AR and β2-AR subtypes differentially interacted with the cAMP sensor EPAC1 to induce distinct signaling pathways. 141 Indeed, although both β-AR subtypes activated the EPAC downstream effector Rap1, only β1-AR was able to regulate EPAC1-induced Rap2 prohypertrophic signaling. Further experiments revealed that the differential interaction of EPAC1 with the scaffolding protein β-arrestin 2 contributes to the specificity of β1-AR and β2-AR signaling.…”

Section: Epac Compartmentationmentioning

confidence: 99%

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

Lezoualc’h

Fazal

Laudette

et al. 2016

Circulation Research

145

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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“…Surprisingly, RACK1 is not the only protein to compete with arrestin for PDE4D5. A recent report suggests that EPAC1, a cAMP effector, binds to arrestin and is recruited to ² 2-AR following adrenergic stimulation [31]. Disruption of the PDE4D5-arrestin complex using cell permeable peptides promoted EPAC-arrestin complex formation to drive hypertrophic signalling events.…”

Section: Beta-arrestinmentioning

confidence: 99%

Location, location, location: PDE4D5 function is directed by its unique N-terminal region

Wills

Ehsan

Whiteley

et al. 2016

Cellular Signalling

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Compartmentalised cAMP SignallingCharacterisation of the cyclic AMP signalling pathway in glycogenolysis as the first "second messenger" system opened the door for study of "cellular signalling" as a Depending on receptor type, cAMP produced at the cell membrane can reach far into the cell or stay localised to its site of production. The distance cAMP travels and its ability to form three-dimensional gradients, triggering activation of cAMP effectors, are determined by the phosphodiesterase (PDE) landscape [8]. Often, PDEs are expressed at low levels yet it is their localisation to demarcated positions within cells that underpins both their effectiveness and function. Indeed, reporter technology devised to visualise cAMP gradient formation following specific receptor activation [9] has confirmed that PDE positioning is crucial to the formation of multiple, simultaneous and spatially distinct cAMP gradients that drive defined physiological responses. PDE familiesPDEs are a vast super-family of distinct, highly regulated enzymes which can be classified based on primary structure into class I, II and III -the largest, class I,

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Specific interactions between Epac1, β-arrestin2 and PDE4D5 regulate β-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling

Cited by 52 publications

References 50 publications

Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death

Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death

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

Location, location, location: PDE4D5 function is directed by its unique N-terminal region

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