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https://www.readbyqxmd.com/read/29111327/overexpression-of-exchange-protein-directly-activated-by-camp-1-epac1-attenuates-bladder-cancer-cell-migration
#1
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/29108990/laminin-1-induces-endocytosis-of-67kda-laminin-receptor-and-protects-neuroscreen-1-cells-against-death-induced-by-serum-withdrawal
#2
Rayudu Gopalakrishna, Usha Gundimeda, Sarah Zhou, Helena Bui, Andrew Davis, Thomas McNeill, William Mack
Although the function of laminin in the basement membrane is known, the function of soluble "neuronal" laminin is unknown. Since laminin is neuroprotective, we determined whether the soluble laminin-1 induces signaling for neuroprotection via its 67KDa laminin-1 receptor (67LR). Treatment of Neuroscreen-1 (NS-1) cells with laminin-1 or YIGSR peptide, which corresponds to a sequence in laminin-1 β1 chain that binds to 67LR, induced a decrease in the cell-surface expression of 67LR and caused its internalization...
November 8, 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/29037982/early-effects-of-epac-depend-on-the-fine-tuning-of-the-sarcoplasmic-reticulum-ca-2-handling-in-cardiomyocytes
#4
N Lezcano, J I E Mariángelo, L Vittone, X H T Wehrens, M Said, C Mundiña-Weilenmann
In cardiac muscle, signaling through cAMP governs many fundamental cellular functions, including contractility, relaxation and automatism. cAMP cascade leads to the activation of the classic protein kinase A but also to the stimulation of the recently discovered exchange protein directly activated by cAMP (Epac). The role of Epac in the regulation of intracellular Ca(2+) homeostasis and contractility in cardiac myocytes is still matter of debate. In this study we showed that the selective Epac activator, 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3', 5'-cyclic monophosphate (8-CPT), produced a positive inotropic effect when adult rat cardiac myocytes were stabilized at low [Ca(2+)]o (0...
October 14, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29027245/epac-induced-ryanodine-receptor-type-2-activation-inhibits-sodium-currents-in-atrial-and-ventricular-murine-cardiomyocytes
#5
Haseeb Valli, Shiraz Ahmad, Sujan Sriharan, Lydia D Dean, Andrew A Grace, Kamalan Jeevaratnam, Hugh R Matthews, Christopher L-H Huang
Acute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca(2+) homeostasis, slows myocardial action potential conduction, and exerts pro-arrhythmic effects. Loose patch-clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na(+) current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage-dependent Na(+) currents...
October 12, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/29023245/education-in-pediatrics-across-the-continuum-epac-first-steps-toward-realizing-the-dream-of-competency-based-education
#6
John S Andrews, James F Bale, Jennifer B Soep, Michele Long, Carol Carraccio, Robert Englander, Deborah Powell
The Education in Pediatrics Across the Continuum (EPAC) Study Group is developing the first competency-based, time-variable progression from undergraduate medical education (UME) to graduate medical education (GME) in the history of medical education in the United States. EPAC, an innovation project sponsored by the Association of American Medical Colleges (AAMC) and supported by the Josiah Macy Jr. Foundation, was developed through a collaboration between 5 medical schools and multiple professional organizations with an interest in undergraduate and graduate medical education...
October 11, 2017: Academic Medicine: Journal of the Association of American Medical Colleges
https://www.readbyqxmd.com/read/29018059/involvement-of-leptin-in-the-molecular-physiology-of-the-placenta
#7
Malena Schanton, Julieta Lorena Maymó, Antonio Pérez-Pérez, Victor Sanchez-Margalet, Cecilia Varone
Leptin is a homeostatic regulator in the placenta where it promotes proliferation, protein synthesis and the expression of tolerogenic maternal response molecules such as HLA-G. Leptin also exerts an anti-apoptotic action in placenta controlling the expression of p53 master cell cycle regulator under different stress conditions. On the other hand, leptin is an integrative target of different placental stimuli. The expression of leptin in placenta is regulated by hCG, insulin, steroids, hypoxia, and many other growth hormones, suggesting that it might have an important endocrine function in the trophoblastic cells...
October 9, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/29016851/mutations-causing-acrodysostosis-2-facilitate-activation-of-phosphodiesterase-4d3
#8
Claire Briet, Arrate Pereda, Catherine Le Stunff, Emmanuelle Motte, Juan de Dios Garcia-Diaz, Guiomar Perez de Nanclares, Nicolas Dumaz, Caroline Silve
Type 2 acrodysostosis (ACRDYS2), a rare developmental skeletal dysplasia characterized by short stature, severe brachydactyly and facial dysostosis, is caused by mutations in the phosphodiesterase (PDE) 4D (PDE4D) gene. Several arguments suggest that the mutations should result in inappropriately increased PDE4D activity, however, no direct evidence supporting this hypothesis has been presented, and the functional consequences of the mutations remain unclear. We evaluated the impact of four different PDE4D mutations causing ACRDYS2 located in different functional domains on the activity of PDE4D3 expressed in Chinese hamster ovary cells...
October 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28987803/long-acting-%C3%AE-2-adrenoreceptor-agonists-suppress-type-1-interferon-expression-in-human-plasmacytoid-dendritic-cells-via-epigenetic-regulation
#9
Chang-Hung Kuo, San-Nan Yang, Yi-Giien Tsai, Chong-Chao Hsieh, Wei-Ting Liao, Li-Chen Chen, Min-Sheng Lee, Hsuan-Fu Kuo, Ching-Hsiung Lin, Chih-Hsing Hung
The combination of inhaled long-acting β2-adrenoreceptor (LABA) and inhaled glucocorticoid (ICS) is a major therapy for asthma. However, the increased risk of infection is still a concern. Plasmacytoid dendritic cells (pDCs) are the predominant cells producing type 1 interferon (IFN) against infection. The effect of LABA/ICS on type 1 IFN expression in human pDCs is unknown. Circulating pDCs were isolated from healthy human subjects and were pretreated with glucocorticoid (GCS), LABA or a cAMP analog, and were stimulated with Toll-like receptor (TLR) agonist CpG (TLR9) or imiquimod (TLR7) in the presence of IL-3...
October 4, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28945820/anthrax-edema-toxin-disrupts-distinct-steps-in-rab11-dependent-junctional-transport
#10
Annabel Guichard, Prashant Jain, Mahtab Moayeri, Ruth Schwartz, Stephen Chin, Lin Zhu, Beatriz Cruz-Moreno, Janet Z Liu, Bernice Aguilar, Andrew Hollands, Stephen H Leppla, Victor Nizet, Ethan Bier
Various bacterial toxins circumvent host defenses through overproduction of cAMP. In a previous study, we showed that edema factor (EF), an adenylate cyclase from Bacillus anthracis, disrupts endocytic recycling mediated by the small GTPase Rab11. As a result, cargo proteins such as cadherins fail to reach inter-cellular junctions. In the present study, we provide further mechanistic dissection of Rab11 inhibition by EF using a combination of Drosophila and mammalian systems. EF blocks Rab11 trafficking after the GTP-loading step, preventing a constitutively active form of Rab11 from delivering cargo vesicles to the plasma membrane...
September 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28939104/new-kids-on-the-block-the-popeye-domain-containing-popdc-protein-family-acting-as-a-novel-class-of-camp-effector-proteins-in-striated-muscle
#11
REVIEW
Thomas Brand, Roland Schindler
The cyclic 3',5'-adenosine monophosphate (cAMP) signalling pathway constitutes an ancient signal transduction pathway present in prokaryotes and eukaryotes. Previously, it was thought that in eukaryotes three effector proteins mediate cAMP signalling, namely protein kinase A (PKA), exchange factor directly activated by cAMP (EPAC) and the cyclic-nucleotide gated channels. However, recently a novel family of cAMP effector proteins emerged and was termed the Popeye domain containing (POPDC) family, which consists of three members POPDC1, POPDC2 and POPDC3...
December 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28912066/the-camp-effectors-pka-and-epac-activate-endothelial-no-synthase-through-pi3k-akt-pathway-in-human-endothelial-cells
#12
Verónica García-Morales, María Luaces-Regueira, Manuel Campos-Toimil
3',5'-Cyclic adenosine monophosphate (cAMP) exerts an endothelium-dependent vasorelaxant action by stimulating endothelial NO synthase (eNOS) activity, and the subsequent NO release, through cAMP protein kinase (PKA) and exchange protein directly activated by cAMP (Epac) activation in endothelial cells. Here, we have investigated the mechanism by which the cAMP-Epac/PKA pathway activates eNOS. cAMP-elevating agents (forskolin and dibutyryl-cAMP) and the joint activation of PKA (6-Bnz-cAMP) and Epac (8-pCPT-2'-O-Me-cAMP) increased cytoplasmic Ca(2+) concentration ([Ca(2+)]c) in ≤30% of fura-2-loaded isolated human umbilical vein endothelial cells (HUVEC)...
September 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28877931/prostaglandin-e2-inhibits-histamine-evoked-ca-2-release-in-human-aortic-smooth-muscle-cells-through-hyperactive-camp-signaling-junctions-and-protein-kinase-a
#13
Emily J A Taylor, Evangelia Pantazaka, Kathryn L Shelley, Colin W Taylor
In human aortic smooth muscle cells, prostaglandin E2 (PGE2) stimulates adenylyl cyclase (AC) and attenuates the increase in intracellular free Ca(2+) concentration evoked by activation of histamine H1 receptors. The mechanisms are not resolved. We show that cAMP mediates inhibition of histamine-evoked Ca(2+) signals by PGE2 Exchange proteins activated by cAMP were not required, but the effects were attenuated by inhibition of cAMP-dependent protein kinase (PKA). PGE2 had no effect on the Ca(2+) signals evoked by protease-activated receptors, heterologously expressed muscarinic M3 receptors, or by direct activation of inositol 1,4,5-trisphosphate (IP3) receptors by photolysis of caged IP3 The rate of Ca(2+) removal from the cytosol was unaffected by PGE2, but PGE2 attenuated histamine-evoked IP3 accumulation...
November 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28864549/atrial-natriuretic-peptide-anp-affects-stimulus-secretion-coupling-of-pancreatic-%C3%AE-cells
#14
Sabrina Undank, Julia Kaiser, Jelena Sikimic, Martina Düfer, Peter Krippeit-Drews, Gisela Drews
ANP influences glucose homeostasis and possibly acts as a link between the cardiovascular system and metabolism, especially in metabolic disorders like diabetes. The present study aimed to evaluate effects of ANP on β-cell function by the use of a β-cell specific knockout of the ANP receptor with guanylate cyclase activity (βGC-A-KO). ANP augmented insulin secretion at the threshold glucose concentration of 6 mM and decreased KATP single channel activity in β-cells of control mice but not of βGC-A-KO mice...
September 1, 2017: Diabetes
https://www.readbyqxmd.com/read/28864467/upregulation-of-epac-1-in-hepatic-stellate-cells-by-prostaglandin-e2-in-liver-fibrosis-is-associated-with-reduced-fibrogenesis
#15
Marlies Schippers, Leonie Beljaars, Eduard Post, Sophie Lotersztajn, Catharina Reker-Smit, Bing Han, Pablo Munoz-Llancao, Martina Schmidt, Klaas Poelstra
Exchange protein activated by cAMP (Epac-1) is an important signaling mechanism for cAMP-mediated effects, yet factors that change Epac-1 levels are unknown. Such factors are relevant because it has been postulated that Epac-1 directly affects fibrogenesis. Prostaglandin E2 (PGE2) is a well-known cAMP activator, and we therefore studied the effects of this cyclo-oxygenase product on Epac-1 expression and on fibrogenesis within the liver. Liver fibrosis was induced by 8 weeks carbon tetrachloride (CCL4) administration to mice...
November 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28851815/epac-rap1-axis-mediated-switch-in-the-response-of-primary-and-metastatic-melanoma-to-cyclic-amp
#16
Carlos I Rodriguez, Edgardo Castro-Perez, Kirthana Prabhakar, Laura Block, B Jack Longley, Jaclyn A Wisinski, Michelle E Kimple, Vijayasaradhi Setaluri
Cyclic AMP (cAMP) is an important second messenger that regulates a wide range of physiological processes. In mammalian cutaneous melanocytes, cAMP-mediated signaling pathways activated by G-protein coupled receptors (GPCRs), like melanocortin 1 receptor (MC1R), play critical roles in melanocyte homeostasis including cell survival, proliferation and pigment synthesis. Impaired cAMP signaling is associated with increased risk of cutaneous melanoma. Whereas mutations in mitogen activated protein kinase (MAPK) pathway components are the most frequent oncogenic drivers of melanoma, the role of cAMP in melanoma is not well understood...
August 29, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28759570/camp-dependent-activation-of-protein-kinase-a-attenuates-respiratory-syncytial-virus-induced-human-airway-epithelial-barrier-disruption
#17
Fariba Rezaee, Terri J Harford, Debra T Linfield, Ghaith Altawallbeh, Ronald J Midura, Andrei I Ivanov, Giovanni Piedimonte
Airway epithelium forms a barrier to the outside world and has a crucial role in susceptibility to viral infections. Cyclic adenosine monophosphate (cAMP) is an important second messenger acting via two intracellular signaling molecules: protein kinase A (PKA) and the guanidine nucleotide exchange factor, Epac. We sought to investigate effects of increased cAMP level on the disruption of model airway epithelial barrier caused by RSV infection and the molecular mechanisms underlying cAMP actions. Human bronchial epithelial cells were infected with RSV-A2 and treated with either cAMP releasing agent, forskolin, or cAMP analogs...
2017: PloS One
https://www.readbyqxmd.com/read/28742159/%C3%AE-adrenergic-signaling-broadly-contributes-to-ltp-induction
#18
Joanna Jȩdrzejewska-Szmek, Vincent Luczak, Ted Abel, Kim T Blackwell
Long-lasting forms of long-term potentiation (LTP) represent one of the major cellular mechanisms underlying learning and memory. One of the fundamental questions in the field of LTP is why different molecules are critical for long-lasting forms of LTP induced by diverse experimental protocols. Further complexity stems from spatial aspects of signaling networks, such that some molecules function in the dendrite and some are critical in the spine. We investigated whether the diverse experimental evidence can be unified by creating a spatial, mechanistic model of multiple signaling pathways in hippocampal CA1 neurons...
July 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28740152/a-cell-based-quantitative-and-isoform-specific-assay-for-exchange-proteins-directly-activated-by-camp
#19
Yingmin Zhu, Fang Mei, Pei Luo, Xiaodong Cheng
Extensive functional studies of the exchange protein directly activated by cAMP (EPAC) family of signaling molecules have demonstrated that EPAC proteins play a fundamental role in several physiological and pathophysiological responses, therefore are attractive drug targets. In this report, the development of a cell-based, medium to high throughput screening assay that is capable of monitoring EPAC-mediated activation of cellular Rap1 in an isoform-specific manner is described. This assay adapts a conventional ELISA format with immobilized RalGDS-RBD as a bait to selectively capture GTP-bound active Rap1...
July 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28731505/calcium-calmodulin-dependent-kinase-2-mediates-epac-induced-spontaneous-transient-outward-currents-in-rat-vascular-smooth-muscle
#20
Edward S A Humphries, Tomoko Kamishima, John M Quayle, Caroline Dart
KEY POINTS: The Ca(2+) and redox-sensing enzyme Ca(2+) /calmodulin-dependent kinase 2 (CaMKII) is a crucial and well-established signalling molecule in the heart and brain. In vascular smooth muscle, which controls blood flow by contracting and relaxing in response to complex Ca(2+) signals and oxidative stress, surprisingly little is known about the role of CaMKII. The vasodilator-induced second messenger cAMP can relax vascular smooth muscle via its effector, exchange protein directly activated by cAMP (Epac), by activating spontaneous transient outward currents (STOCs) that hyperpolarize the cell membrane and reduce voltage-dependent Ca(2+) influx...
September 15, 2017: Journal of Physiology
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