Exchange Protein Directly Activated by cAMP (epac): A Multidomain cAMP Mediator in the Regulation of Diverse Biological Functions

Schmidt, Martina; Dekker, Frank J.; Maarsingh, Harm

doi:10.1124/pr.110.003707

Cited by 234 publications

(269 citation statements)

References 436 publications

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“…This stimulation was unaffected by pharmacological inhibition of PKA, indicating the involvement of alternative cAMP signaling systems, such as exchange protein directly activated by cAMP (Epac) (43). Further studies could confirm this involvement, by use of Epac mutants and Epac-specific agonists such as 8-(4-chlorophenylthio)-2Ј-O-Me-cAMP.…”

Section: Discussionmentioning

confidence: 91%

Sphingomyelin Phosphodiesterase Acid-like 3A (SMPDL3A) Is a Novel Nucleotide Phosphodiesterase Regulated by Cholesterol in Human Macrophages

Traini

Quinn

Sandoval

et al. 2014

Journal of Biological Chemistry

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Background: Cholesterol-loaded macrophages are key mediators of atherosclerosis and demonstrate increased SMPDL3A expression and secretion. Results: SMPDL3A expression is stimulated by cholesterol, liver X receptor ligands, and cAMP and hydrolyzes nucleotide phosphates. Conclusion: SMPDL3A is a nucleotide phosphodiesterase secreted from cholesterol-loaded macrophages. Significance: SMPDL3A possesses a novel enzymatic activity with potential relevance to atherosclerosis.

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Section: Discussionmentioning

confidence: 91%

Sphingomyelin Phosphodiesterase Acid-like 3A (SMPDL3A) Is a Novel Nucleotide Phosphodiesterase Regulated by Cholesterol in Human Macrophages

Traini

Quinn

Sandoval

et al. 2014

Journal of Biological Chemistry

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“…The two isoforms are believed to have different sub‐cellular localization, expression and function (Okumura et al, 2014). This has been widely investigated within the mouse heart (Schmidt et al, 2013). However, a recent study demonstrated that both Epac isoforms are present within mitochondria isolated from adult rat myocytes (Wang et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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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“…Representing a novel category of cAMP mediators, Epac proteins act as specific guanine nucleotide exchange factors (GEFs) for the Ras GTPase family members Rap1 and Rap2 and consequently mediate a wide array of cellular functions including cell division, differentiation, secretion and growth [51]. However, our current understanding of the roles of Epac in chondrocytes is confined to its involvement in mediating anti-inflammatory activity exerted by adenosine 2A receptors during hyaluronan-induced inflammation [20].…”

Section: Discussionmentioning

confidence: 99%

Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures

Juhász

Matta

Somogyi

et al. 2014

Cellular Signalling

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Biomechanical stimuli play important roles in the formation of articular cartilage during early foetal life, and optimal mechanical load is a crucial regulatory factor of adult chondrocyte metabolism and function. In this study, we undertook to analyse mechanotransduction pathways during in vitro chondrogenesis. Chondroprogenitor cells isolated from limb buds of 4-day-old chicken embryos were cultivated as high density cell cultures for 6 days. Mechanical stimulation was carried out by a self-designed bioreactor that exerted uniaxial intermittent cyclic load transmitted by the culture medium as hydrostatic pressure and fluid shear to differentiating cells. The loading scheme (0.05 Hz, 600 Pa; for 30 min) was applied on culturing days 2 and 3, when final commitment and differentiation of chondroprogenitor cells occurred in this model. The applied mechanical load significantly augmented cartilage matrix production and elevated mRNA expression of several cartilage matrix constituents, including collagen type II and aggrecan core protein, as well as matrixproducing hyaluronan synthases through enhanced expression, phosphorylation and nuclear signals of the main chondrogenic transcription factor Sox9. Along with increased cAMP levels, a significantly enhanced protein kinase A (PKA) activity was also detected and CREB, the archetypal downstream transcription factor of PKA signalling, exhibited elevated phosphorylation levels and stronger nuclear signals in response to mechanical stimuli. All the above effects were diminished by the PKA-inhibitor H89. Inhibition of the PKA-independent cAMP-mediators Epac1 and Epac2 with HJC0197 resulted in enhanced cartilage formation, which was additive to that of the mechanical stimulation, implying that the chondrogenesispromoting effect of mechanical load was independent of Epac. At the same time, PP2A activity was reduced following mechanical load and treatments with the PP2A-inhibitor okadaic acid were able to mimic the effects of the intervention. Our results indicate that proper mechanical stimuli augment in vitro cartilage formation via promoting both Juhász and Matta et al. 3 differentiation and matrix production of chondrogenic cells, and the opposing regulation of the PKA/CREB-Sox9 and the PP2A signalling pathways is crucial in this phenomenon.

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Exchange Protein Directly Activated by cAMP (epac): A Multidomain cAMP Mediator in the Regulation of Diverse Biological Functions

Cited by 234 publications

References 436 publications

Sphingomyelin Phosphodiesterase Acid-like 3A (SMPDL3A) Is a Novel Nucleotide Phosphodiesterase Regulated by Cholesterol in Human Macrophages

Sphingomyelin Phosphodiesterase Acid-like 3A (SMPDL3A) Is a Novel Nucleotide Phosphodiesterase Regulated by Cholesterol in Human Macrophages

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

Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures

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