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https://www.readbyqxmd.com/read/28433631/detection-of-camp-and-of-pka-activity-in-saccharomyces-cerevisiae-single-cells-using-fluorescence-resonance-energy-transfer-fret-probes
#1
Sonia Colombo, Serena Broggi, Maddalena Collini, Laura D'Alfonso, Giuseppe Chirico, Enzo Martegani
In Saccharomyces cerevisiae the second messenger cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) play a central role in metabolism regulation, stress resistance and cell cycle progression. To monitor cAMP levels and PKA activity in vivo in single S. cerevisiae cells, we expressed an Epac-based FRET probe and a FRET-based A-kinase activity reporter, which were proven to be useful live-cell biosensors for cAMP levels and PKA activity in mammalian cells. Regarding detection of cAMP in single yeast cells, we show that in wild type strains the CFP/YFP fluorescence ratio increased immediately after glucose addition to derepressed cells, while no changes were observed when glucose was added to a strain that is not able to produce cAMP...
April 19, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28416632/null-epac-mutants-reveal-a-sequential-order-of-versatile-camp-effects-during-drosophila-aversive-odor-learning
#2
Antje Richlitzki, Philipp Latour, Martin Schwärzel
Here, we define a role of the cAMP intermediate EPAC in Drosophila aversive odor learning by means of null epac mutants. Complementation analysis revealed that EPAC acts downstream from the rutabaga adenylyl cyclase and in parallel to protein kinase A. By means of targeted knockdown and genetic rescue we identified mushroom body Kenyon cells (KCs) as a necessary and sufficient site of EPAC action. We provide mechanistic insights by analyzing acquisition dynamics and using the "performance increment" as a means to access the trial-based sequential organization of odor learning...
May 2017: Learning & Memory
https://www.readbyqxmd.com/read/28399451/identification-of-novel-2-benzo-d-isoxazol-3-yl-2-oxo-n-phenylacetohydrazonoyl-cyanide-analoguesas-potent-epac-antagonists
#3
Na Ye, Yingmin Zhu, Zhiqing Liu, Fang C Mei, Haiying Chen, Pingyuan Wang, Xiaodong Cheng, Jia Zhou
Two series of novel EPAC antagonists are designed, synthesized and evaluated in an effort to develop diversified analogues based on the scaffold of the previously identified high-throughput (HTS) hit 1 (ESI-09). Further SAR studies reveal that the isoxazole ring A of 1 can tolerate chemical modifications with either introduction of flexible electron-donating substitutions or structurally restrictedly fusing with a phenyl ring, leading to identification of several more potent and diversified EPAC antagonists (e...
April 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28396013/specific-sirt1-activator-mediated-improvement-in-glucose-homeostasis-requires-sirt1-independent-activation-of-ampk
#4
Sung-Jun Park, Faiyaz Ahmad, Jee-Hyun Um, Alexandra L Brown, Xihui Xu, Hyeog Kang, Hengming Ke, Xuesong Feng, James Ryall, Andrew Philp, Simon Schenk, Myung K Kim, Vittorio Sartorelli, Jay H Chung
The specific Sirt1 activator SRT1720 increases mitochondrial function in skeletal muscle, presumably by activating Sirt1. However, Sirt1 gain of function does not increase mitochondrial function, which raises a question about the central role of Sirt1 in SRT1720 action. Moreover, it is believed that the metabolic effects of SRT1720 occur independently of AMP-activated protein kinase (AMPK), an important metabolic regulator that increases mitochondrial function. Here, we show that SRT1720 activates AMPK in a Sirt1-independent manner and SRT1720 activates AMPK by inhibiting a cAMP degrading phosphodiesterase (PDE) in a competitive manner...
March 14, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28386636/dynamic-monitoring-of-gi-o-protein-mediated-decreases-of-intracellular-camp-by-fret-based-epac-sensors
#5
Ursula Storch, Julie Straub, Serap Erdogmus, Thomas Gudermann, Michael Mederos Y Schnitzler
Analysis of G-protein-coupled receptor (GPCR) signaling, in particular of the second messenger cAMP that is tightly controlled by Gs- and Gi/o-proteins, is a central issue in biomedical research. The classical biochemical method to monitor increases in intracellular cAMP concentrations consists of a radioactive multicellular assay, which is well established, highly sensitive, and reproducible, but precludes continuous spatial and temporal assessment of cAMP levels in single living cells. For this purpose, Förster resonance energy transfer (FRET)-based Epac cAMP sensors are well suitable...
April 6, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28383060/phosphodiesterase-4b-negatively-regulates-endotoxin-activated-interleukin-1-receptor-antagonist-responses-in-macrophages
#6
Jing-Xing Yang, Kou-Chou Hsieh, Yi-Ling Chen, Chien-Kuo Lee, Marco Conti, Tsung-Hsien Chuang, Chin-Pyng Wu, S-L Catherine Jin
Activation of TLR4 by lipopolysaccharide (LPS) induces both pro-inflammatory and anti-inflammatory cytokine production in macrophages. Type 4 phosphodiesterases (PDE4) are key cAMP-hydrolyzing enzymes, and PDE4 inhibitors are considered as immunosuppressors to various inflammatory responses. We demonstrate here that PDE4 inhibitors enhance the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) secretion in LPS-activated mouse peritoneal macrophages, and this response was regulated at the transcriptional level rather than an increased IL-1Ra mRNA stability...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28356349/camp-a-multifaceted-modulator-of-immune-synapse-assembly-and-t-cell-activation
#7
REVIEW
Vijay Bharathi Arumugham, Cosima T Baldari
T Lymphocyte activation involves a substantial reorganization of the membranous and intracellular compartments. Signaling complexes assemble and dismantle in a highly ordered fashion in both compartments and orchestrate the activation of T cells with high sensitivity and specificity. TCR ligation leads to a short burst of cAMP production, which is centrally required for T cell activation; however, sustained elevations in intracellular cAMP concentrations are immunosuppressive. Emerging evidence of the existence of local cAMP pools gleaned from studies on other cell types suggests that cAMP compartmentalization may account, in part, for these opposing effects...
March 29, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28353063/the-microrna-7-mediated-reduction-in-epac-1-contributes-to-vascular-endothelial-permeability-and-enos-uncoupling-in-murine-experimental-retinopathy
#8
Veronica Garcia-Morales, Julian Friedrich, Lysanne M Jorna, Manuel Campos-Toimil, Hans-Peter Hammes, Martina Schmidt, Guido Krenning
AIMS: To investigate the consequences of oxidative stress and hypoxia on EPAC-1 expression during retinopathy. METHODS: Oxygen-induced retinopathy was induced in mice and EPAC-1 expression investigated by immunofluorescence. In silico analyses were used to identify a link between EPAC-1 expression and microRNA-7-5p in endothelial cells and confirmed by western blot analyses on cells expressing microRNA-7-5p. In vitro, endothelial cells were either incubated at 2% oxygen or transfected with microRNA-7-5p, and the effects of these treatments on EPAC-1 expression, endothelial hyperpermeability and NO production were assessed...
March 28, 2017: Acta Diabetologica
https://www.readbyqxmd.com/read/28341741/endogenous-prostaglandin-e2-amplifies-il-33-production-by-macrophages-through-an-e-prostanoid-ep-2-ep4-cyclic-camp-epac-dependent-pathway
#9
Sachin K Samuchiwal, Barbara Balestrieri, Hannah Raff, Joshua A Boyce
When activated through toll-like receptors (TLRs), macrophages generate interleukin-33 (IL-33), an IL-1 family member that induces innate immune responses through ST2 signaling. Lipopolysaccharide (LPS), a TLR4 ligand, induces macrophages to generate prostaglandin E2 (PGE2) through inducible cyclooxygenase (COX)-2 and microsomal PGE2 synthase-1 (mPGES-1) (1). We demonstrate that IL-33 production by bone marrow derived murine macrophages (bmMFs) requires the generation of endogenous PGE2 and the intrinsic expression of EP2 receptors to amplify NF-κB-dependent LPS-induced IL-33 expression via Exchange Protein Activated by cAMP (EPAC)...
March 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28333280/hcg-activates-the-erk1-2-mitogen-activated-protein-kinase-pathway-in-human-endometrial-stromal-cells-transiently-increasing-the-progesterone-receptor-and-regulating-genes-associated-with-endometrial-receptivity
#10
Alejandro Tapia-Pizarro, Sebastián Archiles, Felipe Argandoña, Cecilia Valencia, Keyla Zavaleta, María Cecilia Johnson, Reinaldo González-Ramos, Luigi Devoto
STUDY QUESTION: How does hCG signal in human endometrial stromal cells (ESCs) and what is its role in regulating ESC function? SUMMARY ANSWER: CG signaling in ESCs activates the extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) pathway through exchange protein activated by cAMP (Epac) and transiently increases progesterone receptor (PR) transcript and protein expression and its transcriptional function. WHAT IS KNOWN ALREADY: hCG is one of the earliest embryo-derived secreted signals in the endometrium, which abundantly expresses LH/hCG receptors...
March 14, 2017: Molecular Human Reproduction
https://www.readbyqxmd.com/read/28316073/arrhythmic-effects-of-epac-mediated-ryanodine-receptor-activation-in-langendorff-perfused-murine-hearts-are-associated-with-reduced-conduction-velocity
#11
Mengye Li, Sandeep Hothi, Samantha C Salvage, Kamalan Jeevaratnam, Andrew A Grace, Christopher L-H Huang
Recent papers have attributed arrhythmic substrate in murine RyR2-P2328S hearts to reduced action potential (AP) conduction velocities (CV), reflecting acute functional inhibition and/or reduced expression of sodium channels. We explored for acute effects of direct Epac (exchange protein directly activated by cAMP)-mediated ryanodine receptor-2 (RyR2) activation on arrhythmic substrate and CV. Monophasic action potential recordings demonstrated that initial steady (8-Hz) extrinsic pacing elicited ventricular tachycardia (VT) in 0 of 18 Langendorff-perfused wild-type mouse ventricles before pharmacological intervention...
March 18, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28290664/differential-pharmacophore-definition-of-the-camp-binding-sites-of-neuritogenic-camp-sensor-rapgef2-protein-kinase-a-and-exchange-protein-activated-by-camp-in-neuroendocrine-cells-using-an-adenine-based-scaffold
#12
Andrew C Emery, Ryan A Alvarez, Maribeth V Eiden, Wenqin Xu, Fabrice G Siméon, Lee E Eiden
We recently reported that the adenylate cyclase (AC) inhibitor SQ22,536 (9-tetrahydrofuranyl-adenine) also has inhibitory activity against the neuroendocrine-specific neuritogenic cAMP sensor-Rapgef2 (NCS-Rapgef2), a guanine nucleotide exchanger and activator for the small effector GTPase Rap1. Cell-based assays that distinguish signaling through the three intracellular cAMP sensors NCS-Rapgef2, exchange protein activated by cAMP (Epac), and protein kinase A (PKA), as well as AC, were used. These, collectively, assess the activities of adenine (6-amino-purine) derivatives modified at several positions to enhance selectivity for NCS-Rapgef2 by decreasing affinity for adenylate cyclase (AC), without increasing affinity for PKA or Epac...
March 27, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28283500/in-vitro-interactions-of-epacadostat-and-its-major-metabolites-with-human-efflux-and-uptake-transporters-implications-for-pharmacokinetics-and-drug-interactions
#13
Qiang Zhang, Yan Zhang, Jason Boer, Jack G Shi, Peidi Hu, Sharon Diamond, Swamy Yeleswaram
Epacadostat (EPAC) is a first-in-class, orally active inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and has demonstrated promising clinical activity. In humans, three major plasma metabolites were identified: M9 (a glucuronide-conjugate), M11 (a gut microbiota metabolite), and M12 (a secondary metabolite formed from M11). It is proposed that the biliary excretion of M9, the most abundant metabolite, leads to the enterohepatic circulation of EPAC suggested by the human pharmacokinetics of EPAC...
March 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28283242/exchange-proteins-directly-activated-by-camp-epacs-emerging-therapeutic-targets
#14
REVIEW
Pingyuan Wang, Zhiqing Liu, Haiying Chen, Na Ye, Xiaodong Cheng, Jia Zhou
Exchange proteins directly activated by cAMP (EPACs) are critical cAMP-dependent signaling pathway mediators. The discovery of EPAC proteins has significantly facilitated understanding on cAMP-dependent signaling pathway and efforts along this line open new avenues for developing novel therapeutics for cancer, diabetes, heart failure, inflammation, infections, neurological disorders and other human diseases. Over the past decade, important progress has been made in the identification of EPAC agonists, antagonists and their biological and pharmacological applications...
April 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28278256/activation-of-g-protein-coupled-estrogen-receptor-1-induces-coronary-artery-relaxation-via-epac-rap1-mediated-inhibition-of-rhoa-rho-kinase-pathway-in-parallel-with-pka
#15
Xuan Yu, Qiao Zhang, Yan Zhao, Benjamin J Schwarz, John N Stallone, Cristine L Heaps, Guichun Han
Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac) as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 μM), or ESI-09 (20 μM), or CE3F4 (100 μM), all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0...
2017: PloS One
https://www.readbyqxmd.com/read/28274483/interrogating-cyclic-amp-signaling-using-optical-approaches
#16
REVIEW
Jason Y Jiang, Jeffrey L Falcone, Silvana Curci, Aldebaran M Hofer
Optical reporters for cAMP represent a fundamental advancement in our ability to investigate the dynamics of cAMP signaling. These fluorescent sensors can measure changes in cAMP in single cells or in microdomains within cells as opposed to whole populations of cells required for other methods of measuring cAMP. The first optical cAMP reporters were FRET-based sensors utilizing dissociation of purified regulatory and catalytic subunits of PKA, introduced by Roger Tsien in the early 1990s. The utility of these sensors was vastly improved by creating genetically encoded versions that could be introduced into cells with transfection, the first of which was published in the year 2000...
March 1, 2017: Cell Calcium
https://www.readbyqxmd.com/read/28273829/combined-effects-of-ozone-and-drought-on-the-physiology-and-membrane-lipids-of-two-cowpea-vigna-unguiculata-l-walp-cultivars
#17
Deborah Moura Rebouças, Yuri Maia De Sousa, Matthieu Bagard, Jose Helio Costa, Yves Jolivet, Dirce Fernandes De Melo, Anne Repellin
The interactive effects of drought and ozone on the physiology and leaf membrane lipid content, composition and metabolism of cowpea (Vigna unguiculata (L.) Walp.) were investigated in two cultivars (EPACE-1 and IT83-D) grown under controlled conditions. The drought treatment (three-week water deprivation) did not cause leaf injury but restricted growth through stomatal closure. In contrast, the short-term ozone treatment (130 ppb 12 h daily during 14 day) had a limited impact at the whole-plant level but caused leaf injury, hydrogen peroxide accumulation and galactolipid degradation...
March 3, 2017: Plants (Basel, Switzerland)
https://www.readbyqxmd.com/read/28260059/epac1-overexpression-is-a-prognostic-marker-and-its-inhibition-shows-promising-therapeutic-potential-for-gastric-cancer
#18
Ding-Ping Sun, Chia-Lang Fang, Han-Kun Chen, Kuo-Shan Wen, You-Cheng Hseu, Shih-Ting Hung, Yih-Huei Uen, Kai-Yuan Lin
cAMP signaling controls a variety of cellular functions. In addition to the well-known signal transducer cAMP-dependent protein kinase, a more recently discovered transducer is the exchange protein directly activated by cAMP (EPAC). EPAC responses are mediated by small G proteins, which regulate biologic functions such as cell adhesion, migration and proliferation. Recently, the clinical importance of EPAC1 has received increased attention. This study investigated the correlations between the expression of EPAC1 and various clinicopathologic parameters as well as the survival of the patients with gastric cancer (GC)...
April 2017: Oncology Reports
https://www.readbyqxmd.com/read/28258411/ctrp3-attenuates-cardiac-dysfunction-inflammation-oxidative-stress-and-cell-death-in-diabetic-cardiomyopathy-in-rats
#19
Zhen-Guo Ma, Yu-Pei Yuan, Si-Chi Xu, Wen-Ying Wei, Chun-Ru Xu, Xin Zhang, Qing-Qing Wu, Hai-Han Liao, Jian Ni, Qi-Zhu Tang
AIMS/HYPOTHESIS: Oxidative stress, inflammation and cell death are closely involved in the development of diabetic cardiomyopathy (DCM). C1q/tumour necrosis factor-related protein-3 (CTRP3) has anti-inflammatory properties but its role in DCM remains largely unknown. The aims of this study were to determine whether CTRP3 could attenuate DCM and to clarify the underlying mechanisms. METHODS: Streptozotocin (STZ) was injected intraperitoneally to induce diabetes in Sprague-Dawley rats...
March 3, 2017: Diabetologia
https://www.readbyqxmd.com/read/28216156/exchange-proteins-directly-activated-by-camp-induce-the-proliferation-of-rat-anterior-pituitary-gh3-cells-via-the-activation-of-extracellular-signal-regulated-kinase
#20
Wei Sun, Wei Jiao, Yimin Huang, Ran Li, Zhuo Zhang, Junwen Wang, Ting Lei
Cyclic adenosine 3'-5'-monophosphate (cAMP) plays a crucial role in regulating pituitary cell proliferation and hormone synthesis. Recent evidence suggests that exchange proteins directly activated by cAMP (Epacs) may mediate the effects of cAMP. Here we used rat anterior pituitary GH3 cells as the experiment model to demonstrate that forskolin increased the proliferation of GH3 cells and the phosphorylation of ERK1/2, and these effects were inhibited by PKA or Epac inhibitors. Epac activator 8-pCPT-2'-O-Me-cAMP increased GH3 cell proliferation and this was blocked by ESI-09, an Epac inhibitor...
April 1, 2017: Biochemical and Biophysical Research Communications
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