ArticleThe Journal of biological chemistry2014
Identification and validation of modulators of exchange protein activated by cAMP (Epac) activity: structure-function implications for Epac activation and inhibition.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 20 citations in OpenAlex.
- Role of exchange proteins directly activated by cAMP signaling in vascular remodeling.Pharmacological reviews · 2025Review
- Evolutionary analysis of the Leishmania major orthologues for the newly identified cyclic AMP response proteins.Archives of microbiology · 2025Article
- Essential strategies for the detection of constitutive and ligand-dependent Gi-directed activity of 7TM receptors using bioluminescence resonance energy transfer.bioRxiv : the preprint server for biology · 2024Article
- Article
- Membranes prime the RapGEF EPAC1 to transduce cAMP signaling.Nature communications · 2023Article
- Review
- Review
- A PKA/cdc42 Signaling Axis Restricts Angiogenic Sprouting by Regulating Podosome Rosette Biogenesis and Matrix Remodeling.Scientific reports · 2019Article
- Vasoactive intestinal peptide increases apoptosis of hepatocellular carcinoma by inhibiting the cAMP/Bcl-xL pathway.Cancer science · 2019Article
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
- Attenuation of chemokine receptor function and surface expression as an immunomodulatory strategy employed by human cytomegalovirus is linked to vGPCR US28.Cell communication and signaling : CCS · 2016Article
- Different downstream signalling of CCK1 receptors regulates distinct functions of CCK in pancreatic beta cells.British journal of pharmacology · 2015Article
- Rp-cAMPS Prodrugs Reveal the cAMP Dependence of First-Phase Glucose-Stimulated Insulin Secretion.Molecular endocrinology (Baltimore, Md.) · 2015Article
- The future of EPAC-targeted therapies: agonism versus antagonism.Trends in pharmacological sciences · 2015Review
- Allosteric inhibition of Epac: computational modeling and experimental validation to identify allosteric sites and inhibitors.The Journal of biological chemistry · 2014Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The signaling molecule cAMP primarily mediates its effects by activating PKA and/or exchange protein activated by cAMP (Epac). Epac has been implicated in many responses in cells, but its precise roles have been difficult to define in the absence of Epac inhibitors. Epac, a guanine nucleotide exchange factor for the low molecular weight G protein Rap, is directly activated by cAMP. Using a bioluminescence resonance energy transfer-based assay (CAMYEL) to examine modulators of Epac activity, we took advantage of its intramolecular movement that occurs upon cAMP binding to assess Epac activation. We found that the use of CAMYEL can detect the binding of cAMP analogs to Epac and their modulation of its activity and can distinguish between agonists (cAMP), partial agonists (8-chlorophenylthio-cAMP), and super agonists (8-chlorophenylthio-2'-O-Me-cAMP). The CAMYEL assay can also identify competitive and uncompetitive Epac inhibitors, e.g. (Rp)-cAMPS and CE3F4, respectively. To confirm the results with the CAMYEL assay, we used Swiss 3T3 cells and assessed the ability of cyclic nucleotide analogs to modulate the activity of Epac or PKA, determined by Rap1 activity or VASP phosphorylation, respectively. We used computational molecular modeling to analyze the interaction of analogs with Epac1. The results reveal a rapid means to identify modulators (potentially including allosteric inhibitors) of Epac activity that also provides insight into the mechanisms of Epac activation and inhibition.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.