Rapgef3

Summary

Gene Symbol: Rapgef3
Description: Rap guanine nucleotide exchange factor (GEF) 3
Alias: 2310016P22Rik, 9330170P05Rik, Epac, Epac1, rap guanine nucleotide exchange factor 3, Rap1 guanine-nucleotide-exchange factor directly activated by cAMP, cAMP-GEFI, cAMP-regulated guanine nucleotide exchange factor I, exchange protein directly activated by cAMP 1
Species: mouse
Products:     Rapgef3

Top Publications

  1. Ulucan C, Wang X, Baljinnyam E, Bai Y, Okumura S, Sato M, et al. Developmental changes in gene expression of Epac and its upregulation in myocardial hypertrophy. Am J Physiol Heart Circ Physiol. 2007;293:H1662-72 pubmed
    Although it has been shown that Epac1 mRNA is expressed ubiquitously and Epac2 mRNA predominantly in the brain and endocrine tissues, developmental and pathophysiological changes of these molecules have not been characterized...
  2. Suzuki S, Yokoyama U, Abe T, Kiyonari H, Yamashita N, Kato Y, et al. Differential roles of Epac in regulating cell death in neuronal and myocardial cells. J Biol Chem. 2010;285:24248-59 pubmed publisher
    ..increased by stimulation of Epac at the transcriptional level and was decreased in mice with genetic disruption of Epac1. Epac-induced neuronal apoptosis was attenuated by the silencing of Bim...
  3. Métrich M, Lucas A, Gastineau M, Samuel J, Heymes C, Morel E, et al. Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy. Circ Res. 2008;102:959-65 pubmed publisher
    ..Here, we show that cardiac hypertrophy induced by thoracic aortic constriction increases Epac1 expression in rat myocardium...
  4. Eijkelkamp N, Wang H, Garza Carbajal A, Willemen H, Zwartkruis F, Wood J, et al. Low nociceptor GRK2 prolongs prostaglandin E2 hyperalgesia via biased cAMP signaling to Epac/Rap1, protein kinase Cepsilon, and MEK/ERK. J Neurosci. 2010;30:12806-15 pubmed publisher
    ..Coimmunoprecipitation experiments showed that GRK2 binds to Epac1. In vitro, GRK2 deficiency increased 8-pCPT-induced activation of the downstream effector of Epac, Rap1, and ..
  5. Oestreich E, Malik S, Goonasekera S, Blaxall B, Kelley G, Dirksen R, et al. Epac and phospholipase Cepsilon regulate Ca2+ release in the heart by activation of protein kinase Cepsilon and calcium-calmodulin kinase II. J Biol Chem. 2009;284:1514-22 pubmed publisher
    Recently, we identified a novel signaling pathway involving Epac, Rap, and phospholipase C (PLC)epsilon that plays a critical role in maximal beta-adrenergic receptor (betaAR) stimulation of Ca2+-induced Ca2+ release (CICR) in cardiac ..
  6. Zieba B, Artamonov M, Jin L, Momotani K, Ho R, Franke A, et al. The cAMP-responsive Rap1 guanine nucleotide exchange factor, Epac, induces smooth muscle relaxation by down-regulation of RhoA activity. J Biol Chem. 2011;286:16681-92 pubmed publisher
    ..Isoproterenol-induced increase in Rap1 activity was inhibited by silencing Epac1 in rat aortic SM cells...
  7. Stokman G, Qin Y, Genieser H, Schwede F, De Heer E, Bos J, et al. Epac-Rap signaling reduces cellular stress and ischemia-induced kidney failure. J Am Soc Nephrol. 2011;22:859-72 pubmed publisher
    ..The Epac-Rap signaling pathway is a potent regulator of cell-cell and cell-matrix adhesion...
  8. Hartopo A, Emoto N, Vignon Zellweger N, Suzuki Y, Yagi K, Nakayama K, et al. Endothelin-converting enzyme-1 gene ablation attenuates pulmonary fibrosis via CGRP-cAMP/EPAC1 pathway. Am J Respir Cell Mol Biol. 2013;48:465-76 pubmed publisher
    ..Further, our study identified M2 macrophages as the target cells of CGRP action during this transition. ..
  9. Eijkelkamp N, Linley J, Torres J, Bee L, Dickenson A, Gringhuis M, et al. A role for Piezo2 in EPAC1-dependent mechanical allodynia. Nat Commun. 2013;4:1682 pubmed publisher
    Aberrant mechanosensation has an important role in different pain states. Here we show that Epac1 (cyclic AMP sensor) potentiation of Piezo2-mediated mechanotransduction contributes to mechanical allodynia...

More Information

Publications75

  1. Gong B, Shelite T, Mei F, Ha T, Hu Y, Xu G, et al. Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses. Proc Natl Acad Sci U S A. 2013;110:19615-20 pubmed publisher
    ..We report that deletion of the exchange protein directly activated by cAMP (Epac) gene, Epac1, in mice protects them from an ordinarily lethal dose of rickettsiae...
  2. Yokoyama U, Minamisawa S, Quan H, Akaike T, Jin M, Otsu K, et al. Epac1 is upregulated during neointima formation and promotes vascular smooth muscle cell migration. Am J Physiol Heart Circ Physiol. 2008;295:H1547-55 pubmed publisher
    ..Adenovirus-mediated gene transfer of PKA decreased cell migration, whereas that of Epac1 significantly enhanced cell migration...
  3. Gloerich M, Vliem M, Prummel E, Meijer L, Rensen M, Rehmann H, et al. The nucleoporin RanBP2 tethers the cAMP effector Epac1 and inhibits its catalytic activity. J Cell Biol. 2011;193:1009-20 pubmed publisher
    ..we demonstrate that the nuclear pore component RanBP2 acts as a negative regulator of cAMP signaling through Epac1, a cAMP-regulated guanine nucleotide exchange factor for Rap...
  4. Rah S, Mushtaq M, Nam T, Kim S, Kim U. Generation of cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate by CD38 for Ca2+ signaling in interleukin-8-treated lymphokine-activated killer cells. J Biol Chem. 2010;285:21877-87 pubmed publisher
    ..Furthermore, activation of Rap1, a downstream molecule of Epac, was required for IL-8-induced NAADP formation in LAK cells...
  5. Wang H, Heijnen C, van Velthoven C, Willemen H, Ishikawa Y, Zhang X, et al. Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain. J Clin Invest. 2013;123:5023-34 pubmed publisher
    ..of GPCR kinase 2 (GRK2) in nociceptors promotes cAMP signaling to the guanine nucleotide exchange factor EPAC1 and prolongs the PGE2-induced increase in pain sensitivity (hyperalgesia)...
  6. Murtazina R, Kovbasnjuk O, Zachos N, Li X, Chen Y, Hubbard A, et al. Tissue-specific regulation of sodium/proton exchanger isoform 3 activity in Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) null mice. cAMP inhibition is differentially dependent on NHERF1 and exchange protein directly activated by cAMP in ileum ve. J Biol Chem. 2007;282:25141-51 pubmed
    ..both PKA-dependent and non-PKA-dependent mechanisms were involved, with the latter reproduced by the effect on an EPAC (exchange protein directly activated by cAMP) agonist (8-(4-chlorophenylthio)-2'O-Me-cAMP)...
  7. Amano R, Lee J, Goto N, Harayama H. Evidence for existence of cAMP-Epac signaling in the heads of mouse epididymal spermatozoa. J Reprod Dev. 2007;53:127-33 pubmed
    ..Northern blot analysis and in situ hybridization suggested that Epac1 and Epac2 mRNAs were transcribed in the seminiferous epithelia of the testis...
  8. Aivatiadou E, Ripolone M, Brunetti F, Berruti G. cAMP-Epac2-mediated activation of Rap1 in developing male germ cells: RA-RhoGAP as a possible direct down-stream effector. Mol Reprod Dev. 2009;76:407-16 pubmed publisher
    ..objective was to investigate on a possible cAMP-mediated activation of Rap1 employing a cAMP analogue selective to Epac, the Rap1 activator directly responsive to cAMP, for stimulating cultured testis germ cells...
  9. Zhang L, Malik S, Pang J, Wang H, PARK K, Yule D, et al. Phospholipase C? hydrolyzes perinuclear phosphatidylinositol 4-phosphate to regulate cardiac hypertrophy. Cell. 2013;153:216-27 pubmed publisher
  10. Fazal L, Laudette M, Paula Gomes S, Pons S, Conte C, Tortosa F, et al. Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death. Circ Res. 2017;120:645-657 pubmed publisher
    ..To investigate the role of MitEpac1 (mitochondrial exchange protein directly activated by cAMP 1) in ischemia/reperfusion injury...
  11. Gabrielli M, Martini C, Brandani J, Iustman L, Romero D, del C Vila M. Exchange protein activated by cyclic AMP is involved in the regulation of adipogenic genes during 3T3-L1 fibroblasts differentiation. Dev Growth Differ. 2014;56:143-51 pubmed publisher
    ..IBMX increases cAMP content, which can activate protein kinase A (PKA) and/or EPAC (exchange protein activated by cAMP)...
  12. KLOTH A, Badura A, Li A, Cherskov A, Connolly S, Giovannucci A, et al. Cerebellar associative sensory learning defects in five mouse autism models. elife. 2015;4:e06085 pubmed publisher
    ..Our findings indicate that defects in associative temporal binding of sensory events are widespread in autism mouse models. ..
  13. Hoque K, Woodward O, van Rossum D, Zachos N, Chen L, Leung G, et al. Epac1 mediates protein kinase A-independent mechanism of forskolin-activated intestinal chloride secretion. J Gen Physiol. 2010;135:43-58 pubmed publisher
    ..In contrast, T84 cells with silenced Epac1 had a reduced I(sc) response to FSK, and this response was completely inhibited by H89, but not by the ..
  14. Yang Y, Shu X, Liu D, Shang Y, Wu Y, Pei L, et al. EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation. Neuron. 2012;73:774-88 pubmed publisher
    ..Two variants of EPAC genes including EPAC1 and EPAC2 are cloned and are widely expressed throughout the brain...
  15. Wang H, Robichaux W, Wang Z, Mei F, Cai M, Du G, et al. Inhibition of Epac1 suppresses mitochondrial fission and reduces neointima formation induced by vascular injury. Sci Rep. 2016;6:36552 pubmed publisher
    ..study were to ascertain the physiological functions of exchange proteins directly activated by cAMP isoform 1 (Epac1) in VSMC and to evaluate the potential of Epac1 as therapeutic targets for neointima formation during vascular ..
  16. Moon E, Pyo S. Lipopolysaccharide stimulates Epac1-mediated Rap1/NF-kappaB pathway in Raw 264.7 murine macrophages. Immunol Lett. 2007;110:121-5 pubmed
    ..Here, we investigated whether NF-kappaB can be activated by cAMP production through Epac1-mediated Rap1 activation by using Epac-specific cAMP analogue, 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-..
  17. Oldenburger A, Timens W, Bos S, Smit M, Smrcka A, Laurent A, et al. Epac1 and Epac2 are differentially involved in inflammatory and remodeling processes induced by cigarette smoke. FASEB J. 2014;28:4617-28 pubmed publisher
    ..Using an acute, short-term model of CS exposure, we now studied the role of Epac1, Epac2, and the Epac effector phospholipase-C? (PLC?) in airway inflammation and remodeling in vivo...
  18. Ji Z, Mei F, Cheng X. Epac, not PKA catalytic subunit, is required for 3T3-L1 preadipocyte differentiation. Front Biosci (Elite Ed). 2010;2:392-8 pubmed
    ..We showed that knocking down Epac expression in 3T3-L1 cells using lentiviral based small hairpin RNAs down-regulated peroxisome proliferator-..
  19. Takase H, Matsumoto K, Yamadera R, Kubota Y, Otsu A, Suzuki R, et al. Genome-wide identification of endothelial cell-enriched genes in the mouse embryo. Blood. 2012;120:914-23 pubmed publisher
    ..Thus, the genes identified in our survey show high expression in ECs; further analysis of these genes should facilitate our understanding of the molecular mechanisms of vascular development in the mouse. ..
  20. Li M, Hothi S, Salvage S, Jeevaratnam K, Grace A, Huang C. Arrhythmic effects of Epac-mediated ryanodine receptor activation in Langendorff-perfused murine hearts are associated with reduced conduction velocity. Clin Exp Pharmacol Physiol. 2017;44:686-692 pubmed publisher
    ..We explored for acute effects of direct exchange protein directly activated by cAMP (Epac)-mediated ryanodine receptor-2 (RyR2) activation on arrhythmic substrate and CV...
  21. Jiang Y, Liu L, Curtiss E, Steinle J. Epac1 Blocks NLRP3 Inflammasome to Reduce IL-1? in Retinal Endothelial Cells and Mouse Retinal Vasculature. Mediators Inflamm. 2017;2017:2860956 pubmed publisher
    ..Thus, we hypothesized that Epac1, a downstream mediator of ?-adrenergic receptors, would block TLR4/HMGB1-mediated stimulation of the NLRP3 ..
  22. Patschan D, Patschan S, Wessels J, Becker J, David S, Henze E, et al. Epac-1 activator 8-O-cAMP augments renoprotective effects of syngeneic [corrected] murine EPCs in acute ischemic kidney injury. Am J Physiol Renal Physiol. 2010;298:F78-85 pubmed publisher
    ..In some experiments, EPCs were pretreated with the Epac (exchange protein directly activated by cAMP-1) activator 8-pCPT-2'-O-Me-cAMP (Epac-1 Ac) and the integrin binding ..
  23. Ouyang M, Zhang L, Zhu J, Schwede F, Thomas S. Epac signaling is required for hippocampus-dependent memory retrieval. Proc Natl Acad Sci U S A. 2008;105:11993-7 pubmed publisher
    ..we demonstrate that cAMP and two of its targets, protein kinase A (PKA) and exchange protein activated by cAMP (Epac), are both required for retrieval...
  24. Kopperud R, Rygh C, Karlsen T, Krakstad C, Kleppe R, Hoivik E, et al. Increased microvascular permeability in mice lacking Epac1 (Rapgef3). Acta Physiol (Oxf). 2017;219:441-452 pubmed publisher
    ..This study probes the role of the cAMP mediators rap guanine nucleotide exchange factor 3 and 4 (Epac1 and Epac2) for in vivo control of microvascular macromolecule permeability under ..
  25. García Morales V, Friedrich J, Jorna L, Campos Toimil M, Hammes H, Schmidt M, et al. The microRNA-7-mediated reduction in EPAC-1 contributes to vascular endothelial permeability and eNOS uncoupling in murine experimental retinopathy. Acta Diabetol. 2017;54:581-591 pubmed publisher
    To investigate the consequences of oxidative stress and hypoxia on EPAC-1 expression during retinopathy. Oxygen-induced retinopathy was induced in mice and EPAC-1 expression investigated by immunofluorescence...
  26. Berruti G. CAMP activates Rap1 in differentiating mouse male germ cells: a new signaling pathway mediated by the cAMP-activated exchange factor Epac?. Cell Mol Biol (Noisy-le-grand). 2003;49:381-8 pubmed
    ..Since cAMP-induced Rap1 activation is actually retained to occur through Epac, we checked whether this recently discovered Rap1 exchange factor is expressed in male germ cells...
  27. Almahariq M, Mei F, Wang H, Cao A, Yao S, Soong L, et al. Exchange protein directly activated by cAMP modulates regulatory T-cell-mediated immunosuppression. Biochem J. 2015;465:295-303 pubmed publisher
    ..In the present study we examined the role of the cAMP/EPAC1 (exchange protein directly activated by cAMP) axis in regulatory T-cell (Treg)-mediated immunosuppression using ..
  28. Okumura S, Fujita T, Cai W, Jin M, Namekata I, Mototani Y, et al. Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses. J Clin Invest. 2014;124:2785-801 pubmed publisher
    ..Mice lacking Epac1 (Epac1 KO) exhibited decreased cardiac contractility with reduced phospholamban (PLN) phosphorylation at serine-16,..
  29. Hutchison M, White P. Prostacyclin regulates bone growth via the Epac/Rap1 pathway. Endocrinology. 2015;156:499-510 pubmed publisher
    ..The inhibition of proliferation and ERK activation by celecoxib is also reversed by 8CPT-2Me-cAMP, an activator of Epac, implicating the small G protein Rap1 in the pathway activated by iloprost...
  30. Pereira L, Cheng H, Lao D, Na L, van Oort R, Brown J, et al. Epac2 mediates cardiac ?1-adrenergic-dependent sarcoplasmic reticulum Ca2+ leak and arrhythmia. Circulation. 2013;127:913-22 pubmed publisher
    ..However, cAMP can activate both protein kinase A and an exchange protein directly activated by cAMP (Epac), but their functional interaction is unclear...
  31. Grandoch M, López de Jesús M, Oude Weernink P, Weber A, Jakobs K, Schmidt M. B cell receptor-induced growth arrest and apoptosis in WEHI-231 immature B lymphoma cells involve cyclic AMP and Epac proteins. Cell Signal. 2009;21:609-21 pubmed publisher
    ..BCR signaling to ERK1/2 and Akt requires cyclic AMP-regulated Epac, the latter acting as a guanine nucleotide exchange factor for Rap1 and H-Ras independent of protein kinase A...
  32. Liu L, Jiang Y, Chahine A, Curtiss E, Steinle J. Epac1 agonist decreased inflammatory proteins in retinal endothelial cells, and loss of Epac1 increased inflammatory proteins in the retinal vasculature of mice. Mol Vis. 2017;23:1-7 pubmed
    ..Here, we investigated whether Epac1 is key to the protective effects of ?-adrenergic receptor agonists...
  33. Vang A, Housley W, Dong H, Basole C, Ben Sasson S, Kream B, et al. Regulatory T-cells and cAMP suppress effector T-cells independently of PKA-CREM/ICER: a potential role for Epac. Biochem J. 2013;456:463-73 pubmed publisher
    ..Additionally, activating the cAMP effector Epac (exchange protein directly activated by cAMP) suppressed Teff cells...
  34. Tong J, Liu X, Vickstrom C, Li Y, Yu L, Lu Y, et al. The Epac-Phospholipase C? Pathway Regulates Endocannabinoid Signaling and Cocaine-Induced Disinhibition of Ventral Tegmental Area Dopamine Neurons. J Neurosci. 2017;37:3030-3044 pubmed publisher
    ..effects of 8-CPT-2Me-cAMP on DSI and I-LTD were absent in Epac2 and PLC? knock-out mice, but remained intact in Epac1 knock-out mice...
  35. Misra U, Kaczowka S, Pizzo S. Interaction between TCL1 and Epac1 in the activation of Akt kinases in plasma membranes and nuclei of 8-CPT-2-O-Me-cAMP-stimulated macrophages. Cell Signal. 2008;20:130-8 pubmed
    b>Epac1 is a cAMP-stimulated guanine exchange factor that activates Rap1. The protein product of the T cell leukemia 1 (TCL1) proto-oncogene binds to Akt enhancing its kinase activity...
  36. Gelinas J, Banko J, Peters M, Klann E, Weeber E, Nguyen P. Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus. Learn Mem. 2008;15:403-11 pubmed publisher
    ..However, cAMP may also initiate signaling via a guanine nucleotide exchange protein directly activated by cAMP (Epac). The role of Epac in hippocampal synaptic plasticity is unknown...
  37. Misra U, Pizzo S. Coordinate regulation of forskolin-induced cellular proliferation in macrophages by protein kinase A/cAMP-response element-binding protein (CREB) and Epac1-Rap1 signaling: effects of silencing CREB gene expression on Akt activation. J Biol Chem. 2005;280:38276-89 pubmed
    ..Incubation of macrophages with forskolin also increased Epac1 and Rap1.GTP...
  38. Guibinga G, Murray F, Barron N, Pandori W, Hrustanovic G. Deficiency of the purine metabolic gene HPRT dysregulates microRNA-17 family cluster and guanine-based cellular functions: a role for EPAC in Lesch-Nyhan syndrome. Hum Mol Genet. 2013;22:4502-15 pubmed publisher
    ..Most notably, our data show that the expression of the exchange protein activated by cAMP (EPAC) is blunted in HPRT-deficient human neuron-like cell lines and fibroblast cells from LNS patients, and is altered ..
  39. Herfindal L, Nygaard G, Kopperud R, Krakstad C, Døskeland S, Selheim F. Off-target effect of the Epac agonist 8-pCPT-2'-O-Me-cAMP on P2Y12 receptors in blood platelets. Biochem Biophys Res Commun. 2013;437:603-8 pubmed publisher
    ..inhibits agonist-induced-GPCR-stimulated, but not collagen-stimulated, P-selectin surface expression on Epac1 deficient platelets...
  40. Wilson C, Parker L, Hall C, Smyczek T, Mak J, Crow A, et al. Rasip1 regulates vertebrate vascular endothelial junction stability through Epac1-Rap1 signaling. Blood. 2013;122:3678-90 pubmed publisher
    ..Using an exchange protein directly activated by cyclic adenosine monophosphate 1 (EPAC1)-RAP1-dependent model of nascent junction formation, we demonstrate that a fraction of the RASIP1 protein pool ..
  41. Mediero A, Perez Aso M, Cronstein B. Activation of EPAC1/2 is essential for osteoclast formation by modulating NFκB nuclear translocation and actin cytoskeleton rearrangements. FASEB J. 2014;28:4901-13 pubmed publisher
    ..Rap1 activity was assessed, and signaling events, as well as differentiation in EPAC1/2-knockdown RAW264.7 cells, were studied...
  42. Almahariq M, Chao C, Mei F, Hellmich M, Patrikeev I, Motamedi M, et al. Pharmacological inhibition and genetic knockdown of exchange protein directly activated by cAMP 1 reduce pancreatic cancer metastasis in vivo. Mol Pharmacol. 2015;87:142-9 pubmed publisher
    ..Recently, we have shown that the cAMP sensor protein EPAC1 promotes invasion/migration of pancreatic ductal adenocarcinoma (PDA) in vitro...
  43. Cai W, Fujita T, Hidaka Y, Jin H, Suita K, Prajapati R, et al. Disruption of Epac1 protects the heart from adenylyl cyclase type 5-mediated cardiac dysfunction. Biochem Biophys Res Commun. 2016;475:1-7 pubmed publisher
    ..We therefore generated AC5 transgenic mice (AC5TG) with selective disruption of the Epac1 gene (AC5TG-Epac1KO), and compared their phenotypes with those of AC5TG after chronic isoproterenol (ISO) infusion...
  44. Wiejak J, Dunlop J, Yarwood S. The role of c-Jun in controlling the EPAC1-dependent induction of the SOCS3 gene in HUVECs. FEBS Lett. 2014;588:1556-61 pubmed publisher
    The cyclic AMP sensor, EPAC1, activates AP1-mediated transcription in HUVECs...
  45. Jiang Y, Liu L, Steinle J. Compound 49b Regulates ZO-1 and Occludin Levels in Human Retinal Endothelial Cells and in Mouse Retinal Vasculature. Invest Ophthalmol Vis Sci. 2017;58:185-189 pubmed publisher
    To investigate whether Epac1 is key to Compound 49b's regulation of zonula occluden 1 (ZO-1) and occludin levels in human retinal endothelial cells (REC) and in an Epac1 vascular-specific conditional knockout mouse retina...
  46. Gekel I, Neher E. Application of an Epac activator enhances neurotransmitter release at excitatory central synapses. J Neurosci. 2008;28:7991-8002 pubmed publisher
    ..Using low-frequency (0.2 Hz) electrophysiological recordings in the presence of the Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP (ESCA(1)), we find that Epac activation by this analog accounts on ..
  47. Park T, Baik E, Lee S. Prostaglandin E?-induced intercellular adhesion molecule-1 expression is mediated by cAMP/Epac signalling modules in bEnd.3 brain endothelial cells. Br J Pharmacol. 2013;169:604-18 pubmed publisher
    ..PGE?-induced ICAM-1 expression was reduced by knock-down of Epac1. A PI3K specific inhibitor (LY294002), Akt inhibitor VIII (Akti) and NF-?B inhibitors (Bay-11-7082 and MG-132) ..
  48. Rajagopal S, Kumar D, Mahavadi S, Bhattacharya S, Zhou R, Corvera C, et al. Activation of G protein-coupled bile acid receptor, TGR5, induces smooth muscle relaxation via both Epac- and PKA-mediated inhibition of RhoA/Rho kinase pathway. Am J Physiol Gastrointest Liver Physiol. 2013;304:G527-35 pubmed publisher
    ..OA, but not a selective exchange protein activated by cAMP (Epac) ligand (8-pCPT-2'-O-Me-cAMP), caused phosphorylation of RhoA and the phosphorylation was blocked by the PKA ..
  49. Ster J, de Bock F, Bertaso F, Abitbol K, Daniel H, Bockaert J, et al. Epac mediates PACAP-dependent long-term depression in the hippocampus. J Physiol. 2009;587:101-13 pubmed publisher
    ..we studied the role of an alternative target of cAMP, the exchange protein factor directly activated by cyclic AMP (Epac)...
  50. Shimonaka M, Katagiri K, Nakayama T, Fujita N, Tsuruo T, Yoshie O, et al. Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow. J Cell Biol. 2003;161:417-27 pubmed
    ..Spa1 effectively suppressed this polarization after SLC treatment. This unique characteristic of Rap1 may control chemokine-induced lymphocyte extravasation. ..
  51. Liu X, Chen Y, Tong J, Reynolds A, Proudfoot S, Qi J, et al. Epac Signaling Is Required for Cocaine-Induced Change in AMPA Receptor Subunit Composition in the Ventral Tegmental Area. J Neurosci. 2016;36:4802-15 pubmed publisher
    ..The cocaine-induced increase in GluA2-lacking AMPARs was absent in Epac2-deficient mice but not in Epac1-deficient mice...
  52. Zhao K, Wen R, Wang X, Pei L, Yang Y, Shang Y, et al. EPAC inhibition of SUR1 receptor increases glutamate release and seizure vulnerability. J Neurosci. 2013;33:8861-5 pubmed publisher
    b>EPAC (Exchange Proteins Activated by cAMP) regulates glutamate transmitter release in the central neurons, but a role underlying this regulation has yet to be identified...
  53. Sabbatini M, Chen X, Ernst S, Williams J. Rap1 activation plays a regulatory role in pancreatic amylase secretion. J Biol Chem. 2008;283:23884-94 pubmed publisher
    ..Rap1A/B and the two Rap1 guanine nucleotide exchange factors, Epac1 and CalDAG-GEF III, were identified in mouse pancreatic acini...
  54. Zhou L, Ma S, Yeung P, Wong Y, Tsim K, So K, et al. Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac. Transl Psychiatry. 2016;6:e881 pubmed publisher
    ..However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear...
  55. Khouri C, Dittrich A, Sackett S, Denecke B, Trautwein C, Schaper F. Glucagon counteracts interleukin-6-dependent gene expression by redundant action of Epac and PKA. Biol Chem. 2011;392:1123-34 pubmed publisher
    ..mechanism revealed a redundant action of the signalling molecules exchange protein activated by cyclic AMP (Epac) and protein kinase A. The metabolic hormone glucagon interferes in IL-6-induced gene expression...
  56. Ferrero J, Alvarez A, Ramírez Franco J, Godino M, Bartolomé Martín D, Aguado C, et al. ?-Adrenergic receptors activate exchange protein directly activated by cAMP (Epac), translocate Munc13-1, and enhance the Rab3A-RIM1? interaction to potentiate glutamate release at cerebrocortical nerve terminals. J Biol Chem. 2013;288:31370-85 pubmed publisher
    ..We found that 8-pCPT-2'-O-Me-cAMP, a specific activator of the exchange protein directly activated by cAMP (Epac), mimicked and occluded forskolin-induced potentiation of glutamate release...
  57. Samuchiwal S, Balestrieri B, Raff H, Boyce J. Endogenous prostaglandin E2 amplifies IL-33 production by macrophages through an E prostanoid (EP)2/EP4-cAMP-EPAC-dependent pathway. J Biol Chem. 2017;292:8195-8206 pubmed publisher
    ..receptors to amplify NF-?B-dependent, LPS-induced IL-33 expression via exchange protein activated by cAMP (EPAC)...
  58. Sun L, Kondeti V, Xie P, Raparia K, Kanwar Y. Epac1-mediated, high glucose-induced renal proximal tubular cells hypertrophy via the Akt/p21 pathway. Am J Pathol. 2011;179:1706-18 pubmed publisher
    ..We investigated the role of exchange protein activated by cAMP 1(Epac1), which activates Rap-family G proteins in cellular hypertrophy...
  59. Yan J, Mei F, Cheng H, Lao D, Hu Y, Wei J, et al. Enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic AMP isoform 1. Mol Cell Biol. 2013;33:918-26 pubmed publisher
    ..To explore the physiological functions of Epac1, we generated Epac1 knockout mice...
  60. Lehrke M, Kahles F, Makowska A, Tilstam P, Diebold S, Marx J, et al. PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner. J Mol Cell Cardiol. 2015;81:23-33 pubmed publisher
    ..Specific activation of the cAMP effector Epac, but not PKA activation mimicked the effects of roflumilast on VCAM-1 expression...
  61. Weissman J, Ma J, Essex A, Gao Y, Burstein E. G-protein-coupled receptor-mediated activation of rap GTPases: characterization of a novel Galphai regulated pathway. Oncogene. 2004;23:241-9 pubmed
    ..A constitutively active mutant of Galphai2 also mediated Ras/rap-dependent responses. These data indicate that GPCRs coupled to pertussis-toxin-sensitive G-proteins activate Rap through a Galpha subunit, C3G, and Src-dependent pathway. ..
  62. Chen C, Du J, Feng W, Song Y, Lu Z, Xu M, et al. ?-Adrenergic receptors stimulate interleukin-6 production through Epac-dependent activation of PKC?/p38 MAPK signalling in neonatal mouse cardiac fibroblasts. Br J Pharmacol. 2012;166:676-88 pubmed publisher
    ..The translocation of PKC? was determined by immunoblotting the soluble and particulate fractions. Expression of Epac1 or PKC? was knocked down by the corresponding, adenovirus-mediated, small hairpin RNA (shRNA)...
  63. Nijholt I, Dolga A, Ostroveanu A, Luiten P, Schmidt M, Eisel U. Neuronal AKAP150 coordinates PKA and Epac-mediated PKB/Akt phosphorylation. Cell Signal. 2008;20:1715-24 pubmed publisher
    ..pathways initiated by cAMP, cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epac1 and Epac2) on PKB/Akt phosphorylation in primary cortical neurons and HT-4 cells...
  64. Muñoz Llancao P, Henríquez D, Wilson C, Bodaleo F, Boddeke E, Lezoualc h F, et al. Exchange Protein Directly Activated by cAMP (EPAC) Regulates Neuronal Polarization through Rap1B. J Neurosci. 2015;35:11315-29 pubmed publisher
    ..In contrast, pharmacological inhibition of EPAC delayed neuronal polarity. Genetic manipulations to inactivate EPAC1 using either shRNA or neurons derived from EPAC1 knock-out (KO) mice led to axon elongation and polarization ..
  65. Kaneko K, Xu P, Cordonier E, Chen S, Ng A, Xu Y, et al. Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions. Cell Rep. 2016;16:3003-3015 pubmed publisher
    ..Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment. ..
  66. Aoyama M, Kawase H, Bando Y, Monji A, Murohara T. Dipeptidyl Peptidase 4 Inhibition Alleviates Shortage of Circulating Glucagon-Like Peptide-1 in Heart Failure and Mitigates Myocardial Remodeling and Apoptosis via the Exchange Protein Directly Activated by Cyclic AMP 1/Ras-Related Protein 1 Axis. Circ Heart Fail. 2016;9:e002081 pubmed publisher
    ..levels observed in TAC, thereby augmented cAMP signaling effectors (protein kinase A [PKA] and exchange protein directly activated by cAMP 1 [EPAC1]). In vitro assay revealed distinct roles of PKA and EPAC1 in cardiac apoptosis...