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https://www.readbyqxmd.com/read/29167062/mechanistic-insights-into-the-detection-of-free-fatty-and-bile-acids-by-ileal-glucagon-like-peptide-1-secreting-cells
#1
Deborah A Goldspink, Van B Lu, Lawrence J Billing, Pierre Larraufie, Gwen Tolhurst, Fiona M Gribble, Frank Reimann
OBJECTIVES: The aim of this study was to investigate the electrical properties of ileal Glucagon-like peptide 1 (GLP-1) secreting L-cells using murine organoid cultures and the electrophysiological and intracellular signaling pathways recruited following activation of the Gαq-coupled free fatty acid receptors FFA1 and Gαs-coupled bile acid receptors GPBAR1. METHODS: Experiments were performed using ileal organoids generated from mice transgenically expressing fluorescent reporters (Epac2-camps and GCaMP3) under control of the proglucagon promoter...
November 11, 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29111327/overexpression-of-exchange-protein-directly-activated-by-camp-1-epac1-attenuates-bladder-cancer-cell-migration
#2
Hirona Ichikawa, Momoe Itsumi, Shunichi Kajioka, Tomoko Maki, Ken Lee, Makoto Tomita, Shoji Yamaoka
Exchange protein directly activated by cAMP (EPAC) is a mediator of a cAMP signaling pathway that is independent of protein kinase A. EPAC has two isoforms (EPAC1 and EPAC2) and is a cAMP-dependent guanine nucleotide exchange factor for the small GTPases, Rap1 and Rap2. Recent studies suggest that EPAC1 has both positive and negative influences on cancer and is involved in cell proliferation, apoptosis, migration and metastasis. We report that EPAC1 and EPAC2 expression levels were significantly lower in bladder cancer tissue than in normal bladder tissue...
October 27, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29100797/structure-activity-relationships-of-2-substituted-phenyl-n-phenyl-2-oxoacetohydrazonoyl-cyanides-as-novel-antagonists-of-exchange-proteins-directly-activated-by-camp-epacs
#3
Zhiqing Liu, Yingmin Zhu, Haiying Chen, Pingyuan Wang, Fang C Mei, Na Ye, Xiaodong Cheng, Jia Zhou
Exchange proteins directly activated by cAMP (EPACs) are critical cAMP-dependent signaling pathway mediators that play important roles in cancer, diabetes, heart failure, inflammations, infections, neurological disorders and other human diseases. EPAC specific modulators are urgently needed to explore EPAC's physiological function, mechanism of action and therapeutic applications. On the basis of a previously identified EPAC specific inhibitor hit ESI-09, herein we have designed and synthesized a novel series of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as potent EPAC inhibitors...
December 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28827743/mir-125a-mir-139-and-mir-324-contribute-to-urocortin-protection-against-myocardial-ischemia-reperfusion-injury
#4
Ignacio Díaz, Eva Calderón-Sánchez, Raquel Del Toro, Javier Ávila-Médina, Eva Sánchez de Rojas-de Pedro, Alejandro Domínguez-Rodríguez, Juan Antonio Rosado, Abdelkrim Hmadcha, Antonio Ordóñez, Tarik Smani
Urocortin 1 and 2 (Ucn-1 and Ucn-2) have established protective actions against myocardial ischemia-reperfusion (I/R) injuries. However, little is known about their role in posttranscriptional regulation in the process of cardioprotection. Herein, we investigated whether microRNAs play a role in urocortin-induced cardioprotection. Administration of Ucn-1 and Ucn-2 at the beginning of reperfusion significantly restored cardiac function, as evidenced ex vivo in Langendorff-perfused rat hearts and in vivo in rat subjected to I/R...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28821815/epac1-deficient-mice-have-bleeding-phenotype-and-thrombocytes-with-decreased-gpib%C3%AE-expression
#5
Gyrid Nygaard, Lars Herfindal, Kathrine S Asrud, Ronja Bjørnstad, Reidun K Kopperud, Eystein Oveland, Frode S Berven, Lene Myhren, Erling A Hoivik, Turid Helen Felli Lunde, Marit Bakke, Stein O Døskeland, Frode Selheim
Epac1 (Exchange protein directly activated by cAMP 1) limits fluid loss from the circulation by tightening the endothelial barrier. We show here that Epac1(-/-) mice, but not Epac2(-/-) mice, have prolonged bleeding time, suggesting that Epac1 may limit fluid loss also by restraining bleeding. The Epac1(-/-) mice had deficient in vitro secondary hemostasis. Quantitative comprehensive proteomics analysis revealed that Epac1(-/-) mouse platelets (thrombocytes) had unbalanced expression of key components of the glycoprotein Ib-IX-V (GPIb-IX-V) complex, with decrease of GP1bβ and no change of GP1bα...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28603838/compartmentalized-camp-responses-to-prostaglandin-ep2-receptor-activation-in-human-airway-smooth-muscle-cells
#6
Shailesh R Agarwal, Kathryn Miyashiro, Htun Latt, Rennolds S Ostrom, Robert D Harvey
BACKGROUND AND PURPOSE: Previous studies indicate that prostaglandin EP2 receptors selectively couple to AC2 in non-lipid raft domains of airway smooth muscle (ASM) cells, where they regulate specific cAMP-dependent responses. The goal of the present study was to identify the cellular microdomains where EP2 receptors stimulate cAMP production. EXPERIMENTAL APPROACH: FRET-based cAMP biosensors were targeted to different subcellular locations of primary human ASM cells...
August 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28558129/somatostatin-depresses-the-excitability-of-subicular-bursting-cells-roles-of-inward-rectifier-k-channels-kcnq-channels-and-epac
#7
Binqi Hu, Nicholas I Cilz, Saobo Lei
The hippocampus is a crucial component for cognitive and emotional processing. The subiculum provides much of the output for this structure but the modulation and function of this region is surprisingly under-studied. The neuromodulator somatostatin (SST) interacts with five subtypes of SST receptors (sst1 to sst5 ) and each of these SST receptor subtypes is coupled to Gi proteins resulting in inhibition of adenylyl cyclase (AC) and decreased level of intracellular cAMP. SST modulates many physiological functions including cognition, emotion, autonomic responses and locomotion...
September 2017: Hippocampus
https://www.readbyqxmd.com/read/28546426/guanine-nucleotide-exchange-factor-epac2-dependent-activation-of-the-gtp-binding-protein-rap2a-mediates-camp-dependent-growth-arrest-in-neuroendocrine-cells
#8
Andrew C Emery, Wenqin Xu, Maribeth V Eiden, Lee E Eiden
First messenger-dependent activation of MAP kinases in neuronal and endocrine cells is critical for cell differentiation and function and requires guanine nucleotide exchange factor (GEF)-mediated activation of downstream Ras family small GTPases, which ultimately lead to ERK, JNK, and p38 phosphorylation. Because there are numerous GEFs and also a host of Ras family small GTPases, it is important to know which specific GEF-small GTPase dyad functions in a given cellular process. Here we investigated the upstream activators and downstream effectors of signaling via the GEF Epac2 in the neuroendocrine NS-1 cell line...
July 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28476660/%C3%AE-adrenergic-induced-sr-ca-2-leak-is-mediated-by-an-epac-nos-pathway
#9
Laëtitia Pereira, Dan J Bare, Samuel Galice, Thomas R Shannon, Donald M Bers
Cardiac β-adrenergic receptors (β-AR) and Ca(2+)-Calmodulin dependent protein kinase (CaMKII) regulate both physiological and pathophysiological Ca(2+) signaling. Elevated diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) contributes to contractile dysfunction in heart failure and to arrhythmogenesis. β-AR activation is known to increase SR Ca(2+) leak via CaMKII-dependent phosphorylation of the ryanodine receptor. Two independent and reportedly parallel pathways have been implicated in this β-AR-CaMKII cascade, one involving exchange protein directly activated by cAMP (Epac2) and another involving nitric oxide synthase 1 (NOS1)...
July 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28445587/cb1-receptors-down-regulate-a-camp-epac2-plc-pathway-to-silence-the-nerve-terminals-of-cerebellar-granule-cells
#10
Beatris Alonso, David Bartolomé-Martín, José Javier Ferrero, Jorge Ramírez-Franco, Magdalena Torres, José Sánchez-Prieto
Cannabinoid receptors mediate short-term retrograde inhibition of neurotransmitter release, as well as long-term depression of synaptic transmission at excitatory synapses. The responses of individual nerve terminals in VGLUT1-pHluorin transfected cerebellar granule cells to cannabinoids have shown that prolonged activation of cannabinoid type 1 receptors (CB1Rs) silences a subpopulation of previously active synaptic boutons. Adopting a combined pharmacological and genetic approach to study the molecular mechanisms of CB1R-induced silencing, we found that adenylyl cyclase inhibition decreases cAMP levels while it increases the number of silent synaptic boutons and occludes the induction of further silencing by the cannabinoid agonist HU-210...
August 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28389413/influence-of-cell-confluence-on-the-camp-signalling-pathway-in-vascular-smooth-muscle-cells
#11
M Belacel-Ouari, L Zhang, F Hubert, R Assaly, R Gerbier, R Jockers, F Dauphin, P Lechêne, R Fischmeister, B Manoury, V Leblais
The influence of cell confluence on the β-adrenoceptor (β-AR)/cAMP/phosphodiesterase (PDE) pathway was investigated in cultured rat aortic smooth muscle cells (RASMCs). Cells were plated either at low density (LD: 3·10(3)cells/cm(2)) or high density (HD: 3·10(4)cells/cm(2)) corresponding to non-confluent or confluent cells, respectively, on the day of experiment. β-AR-stimulated cAMP was monitored in real-time using the fluorescence resonance energy transfer (FRET)-based cAMP sensor, Epac2-camps. A brief application (15s) of the β-AR agonist isoprenaline (Iso) induced a typical transient FRET signal, reflecting cAMP production followed by its rapid degradation...
April 4, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28331191/identification-of-a-novel-small-molecule-partial-agonist-for-the-cyclic-amp-sensor-epac1
#12
Euan Parnell, Stuart P McElroy, Jolanta Wiejak, Gemma L Baillie, Alison Porter, David R Adams, Holger Rehmann, Brian O Smith, Stephen J Yarwood
Screening of a carefully selected library of 5,195 small molecules identified 34 hit compounds that interact with the regulatory cyclic nucleotide-binding domain (CNB) of the cAMP sensor, EPAC1. Two of these hits (I942 and I178) were selected for their robust and reproducible inhibitory effects within the primary screening assay. Follow-up characterisation by ligand observed nuclear magnetic resonance (NMR) revealed direct interaction of I942 and I178 with EPAC1 and EPAC2-CNBs in vitro. Moreover, in vitro guanine nucleotide exchange factor (GEF) assays revealed that I942 and, to a lesser extent, I178 had partial agonist properties towards EPAC1, leading to activation of EPAC1, in the absence of cAMP, and inhibition of GEF activity in the presence of cAMP...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28209735/the-epac-phospholipase-c%C3%AE%C2%B5-pathway-regulates-endocannabinoid-signaling-and-cocaine-induced-disinhibition-of-ventral-tegmental-area-dopamine-neurons
#13
Jiaqing Tong, Xiaojie Liu, Casey Vickstrom, Yan Li, Laikang Yu, Youming Lu, Alan V Smrcka, Qing-Song Liu
Exchange protein directly activated by cAMP (Epac) is a direct effector for the ubiquitous second messenger cAMP. Epac activates the phospholipase Cε (PLCε) pathway. PLCβ has been linked to the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Here, we report that Epac facilitates endocannabinoid-mediated retrograde synaptic depression through activation of PLCε. Intracellular loading of a selective Epac agonist 8-CPT-2Me-cAMP into ventral tegmental area (VTA) dopamine neurons enabled previously ineffective stimuli to induce depolarization-induced suppression of inhibition (DSI) and long-term depression of IPSCs (I-LTD) in the VTA...
March 15, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28097390/a-role-of-plc-pkc-dependent-pathway-in-glp-1-stimulated-insulin-secretion
#14
REVIEW
Makoto Shigeto, Chae Young Cha, Patrik Rorsman, Kohei Kaku
Glucagon-like peptide-1 (GLP-1) is an endogenous glucose-lowering hormone and GLP-1 receptor agonists are currently being used as antidiabetic drugs clinically. The canonical signalling pathway (including cAMP, Epac2, protein kinase A (PKA) and KATP channels) is almost universally accepted as the main mechanism of GLP-1-stimulated insulin secretion. This belief is based on in vitro studies that used nanomolar (1-100 nM) concentrations of GLP-1. Recently, it was found that the physiological concentrations (1-10 pM) of GLP-1 also stimulate insulin secretion from isolated islets, induce membrane depolarization and increase of intracellular [Ca(2+)] in isolated β cells/pancreatic islets...
April 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/27984207/acquired-exchange-protein-directly-activated-by-cyclic-adenosine-monophosphate-activity-induced-by-p38-mitogen-activated-protein-kinase-in-primary-afferent-neurons-contributes-to-sustaining-postincisional-nociception
#15
Megumi Matsuda, Kentaro Oh-Hashi, Isao Yokota, Teiji Sawa, Fumimasa Amaya
BACKGROUND: The molecular mechanisms responsible for sustained pain after tissue injury are largely unknown. The aim of this study was to clarify the role of exchange protein directly activated by cyclic adenosine monophosphate (EPAC) in sustained postincisional nociception, using tissue injury-induced nociceptor priming, and involvement of p38 mitogen-activated protein kinase (p38MAPK) in EPAC-mediated nociceptor priming. METHODS: Plantar incisions were made in the hind paws of Sprague-Dawley rats (n = 144)...
January 2017: Anesthesiology
https://www.readbyqxmd.com/read/27933093/long-term-consumption-of-an-obesogenic-high-fat-diet-prior-to-ischemia-reperfusion-mediates-cardioprotection-via-epac1-dependent-signaling
#16
F Edland, A Wergeland, R Kopperud, K S Åsrud, E A Hoivik, S L Witsø, R Æsøy, L Madsen, K Kristiansen, M Bakke, S O Døskeland, A K Jonassen
BACKGROUND: Obesity is still considered a risk factor for cardiovascular disease, although more recent knowledge also suggests obesity to be associated with reduced morbidity and mortality - the "obesity paradox". This study explores if long-term feeding of an obesogenic high fat diet renders the myocardium less susceptible to ischemic-reperfusion induced injury via Epac-dependent signaling. METHODS: Wild type (wt), Epac1 (Epac1(-/-)) and Epac2 (Epac2(-/-)) deficient mice were fed a high fat (HFD) or normal chow diet (ND) for 33 ± 1 weeks...
2016: Nutrition & Metabolism
https://www.readbyqxmd.com/read/27900608/interaction-of-epac-with-non-canonical-cyclic-nucleotides
#17
REVIEW
Holger Rehmann
Epac1 and Epac2 are cyclic nucleotide-binding (CNB) domain containing proteins, which were originally identified as cAMP-regulated guanine nucleotide exchange factors (GEFs) for the small G-protein Rap. Therefore, Epac proteins founded next to protein kinase A (PKA) and cyclic nucleotide-regulated ion channels the third group of cAMP-responsive proteins in higher organisms. Epac proteins are involved in the regulation of several physiological processes. In particular Epac1 mediates the regulation of molecular processes underlying cell adhesion and mobility...
2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27867203/epac2a-null-mice-exhibit-obesity-prone-nature-more-susceptible-to-leptin-resistance
#18
M Hwang, Y Go, J-H Park, S-K Shin, S E Song, B-C Oh, S-S Im, I Hwang, Y H Jeon, I-K Lee, S Seino, D-K Song
BACKGROUND: The exchange protein directly activated by cAMP (Epac), which is primarily involved in cAMP signaling, has been known to be essential for controlling body energy metabolism. Epac has two isoforms: Epac1 and Epac2. The function of Epac1 on obesity was unveiled using Epac1 knockout (KO) mice. However, the role of Epac2 in obesity remains unclear. METHODS: To evaluate the role of Epac2 in obesity, we used Epac2a KO mice, which is dominantly expressed in neurons and endocrine tissues...
February 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/27865066/newly-synthesized-camp-is-integrated-at-a-membrane-protein-complex-signalosome-to-ensure-receptor-response-specificity
#19
Raquel Guinzberg, Antonio Díaz-Cruz, Carlos Acosta-Trujillo, María Magdalena Vilchis-Landeros, Héctor Vázquez-Meza, Carlos Lozano-Flores, Natalia Chiquete-Felix, Alfredo Varela-Echavarría, Salvador Uribe-Carvajal, Héctor Riveros-Rosas, Enrique Piña
Spatiotemporal regulation of cAMP within the cell is required to achieve receptor-specific responses. The mechanism through which the cell selects a specific response to newly synthesized cAMP is not fully understood. In hepatocyte plasma membranes, we identified two functional and independent cAMP-responsive signaling protein macrocomplexes that produce, use, degrade, and regulate their own nondiffusible (sequestered) cAMP pool to achieve their specific responses. Each complex responds to the stimulation of an adenosine G protein-coupled receptor (Ado-GPCR), bound to either A2A or A2B , but not simultaneously to both...
January 2017: FEBS Journal
https://www.readbyqxmd.com/read/27649969/epac2-rap1-signaling-regulates-reactive-oxygen-species-production-and-susceptibility-to-cardiac-arrhythmias
#20
Zhaokang Yang, Hannah M Kirton, Moza Al-Owais, Jérôme Thireau, Sylvain Richard, Chris Peers, Derek S Steele
AIMS: In the heart, β1-adrenergic signaling involves cyclic adenosine monophosphate (cAMP) acting via both protein kinase-A (PKA) and exchange protein directly activated by cAMP (Epac): a guanine nucleotide exchange factor for the small GTPase Rap1. Inhibition of Epac-Rap1 signaling has been proposed as a therapeutic strategy for both cancer and cardiovascular disease. However, previous work suggests that impaired Rap1 signaling may have detrimental effects on cardiac function. The aim of the present study was to investigate the influence of Epac2-Rap1 signaling on the heart using both in vivo and in vitro approaches...
July 20, 2017: Antioxidants & Redox Signaling
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