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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
#1
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
#2
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...
November 30, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27867203/epac2a-null-mice-exhibit-obesity-prone-nature-more-susceptible-to-leptin-resistance
#3
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...
November 21, 2016: 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
#4
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 new 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 non-diffusible (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...
November 19, 2016: FEBS Journal
https://www.readbyqxmd.com/read/27649969/epac2-rap1-signaling-regulates-reactive-oxygen-species-production-and-susceptibility-to-cardiac-arrhythmias
#5
Zhaokang Yang, Hannah Kirton, Moza Al-Owais, Jerôme Thireau, Sylvain Richard, Derek Steele, Chris Peers
AIMS: In the heart, β<sub>1</sub>-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...
September 21, 2016: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/27598965/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
#6
L Zhou, S L Ma, P K K Yeung, Y H Wong, K W K Tsim, K F So, L C W Lam, S K Chung
Intracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). 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...
2016: Translational Psychiatry
https://www.readbyqxmd.com/read/27554468/white-adipocyte-adiponectin-exocytosis-is-stimulated-via-%C3%AE-3-adrenergic-signaling-and-activation-of-epac1-catecholamine-resistance-in-obesity-and-type-2-diabetes
#7
Ali M Komai, Saliha Musovic, Eduard Peris, Ahmed Alrifaiy, Mickaël F El Hachmane, Marcus Johansson, Ingrid Wernstedt Asterholm, Charlotta S Olofsson
We investigated the physiological regulation of adiponectin exocytosis in health and metabolic disease by a combination of membrane capacitance patch-clamp recordings and biochemical measurements of short-term (30 min incubations) adiponectin secretion. Adrenaline or the β3 adrenergic receptor agonist CL 316,243 (CL) stimulated adiponectin exocytosis/secretion in cultured 3T3-L1 and in primary subcutaneous mouse adipocytes and the stimulation was inhibited by the Epac (Exchange Protein directly Activated by cAMP) antagonist ESI-09...
August 23, 2016: Diabetes
https://www.readbyqxmd.com/read/27549789/the-role-of-epac-in-the-heart
#8
Takayuki Fujita, Masanari Umemura, Utako Yokoyama, Satoshi Okumura, Yoshihiro Ishikawa
As one of the most important second messengers, 3',5'-cyclic adenosine monophosphate (cAMP) mediates various extracellular signals including hormones and neurotransmitters, and induces appropriate responses in diverse types of cells. Since cAMP was formerly believed to transmit signals through only two direct target molecules, protein kinase A and the cyclic nucleotide-gated channel, the sensational discovery in 1998 of another novel direct effecter of cAMP [exchange proteins directly activated by cAMP (Epac)] attracted a great deal of scientific interest in cAMP signaling...
August 22, 2016: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/27379015/role-of-epac-in-camp-mediated-actions-in-adrenocortical-cells
#9
REVIEW
Aurélia E Lewis, Reidun Aesoy, Marit Bakke
Adrenocorticotropic hormone regulates adrenal steroidogenesis mainly via the intracellular signaling molecule cAMP. The effects of cAMP are principally relayed by activating protein kinase A (PKA) and the more recently discovered exchange proteins directly activated by cAMP 1 and 2 (EPAC1 and EPAC2). While the intracellular roles of PKA have been extensively studied in steroidogenic tissues, those of EPACs are only emerging. EPAC1 and EPAC2 are encoded by the genes RAPGEF3 and RAPGEF4, respectively. Whereas EPAC1 is ubiquitously expressed, the expression of EPAC2 is more restricted, and typically found in endocrine tissues...
2016: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/27277757/epac1-knockdown-inhibits-the-proliferation-of-ovarian-cancer-cells-by-inactivating-akt-cyclin-d1-cdk4-pathway-in-vitro-and-in-vivo
#10
Meng Gao, Yanyan Ma, Robert C Bast, Yue Li, Lu Wan, Yanping Liu, Yingshuo Sun, Zhenghui Fang, Lining Zhang, Xiaoyan Wang, Zengtao Wei
Ovarian cancer is the leading cause of death among gynecological malignancies, and high grade serous ovarian carcinoma is the most common and most aggressive subtype. Recently, it was demonstrated that cAMP mediates protein kinase A-independent effects through Epac (exchange protein directly activated by cAMP) proteins. Epac proteins, including Epac1 and Epac2, are implicated in several diverse cellular responses, such as insulin secretion, exocytosis, cellular calcium handling and formation of cell-cell junctions...
July 2016: Medical Oncology
https://www.readbyqxmd.com/read/27190593/functionalized-n-n-diphenylamines-as-potent-and-selective-epac2-inhibitors
#11
Christopher T Wild, Yingmin Zhu, Ye Na, Fang Mei, Marcus A Ynalvez, Haiying Chen, Xiaodong Cheng, Jia Zhou
N,N-Diphenylamines were discovered as potent and selective EPAC2 inhibitors. A study was conducted to determine the structure-activity relationships in a series of inhibitors of which several compounds displayed submicromolar potencies. Selectivity over the related EPAC1 protein was also demonstrated. Computational modeling reveals an allosteric site that is distinct from the cAMP binding domain shared by both EPAC isoforms, providing a theory with regards to subtype selectivity.
May 12, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27122037/epac-signaling-is-required-for-cocaine-induced-change-in-ampa-receptor-subunit-composition-in-the-ventral-tegmental-area
#12
Xiaojie Liu, Yao Chen, Jiaqing Tong, Ashley M Reynolds, Sarah C Proudfoot, Jinshun Qi, Peter Penzes, Youming Lu, Qing-Song Liu
UNLABELLED: Exchange protein directly activated by cAMP (Epac) and protein kinase A (PKA) are intracellular receptors for cAMP. Although PKA and its downstream effectors have been studied extensively in the context of drug addiction, whether and how Epac regulates cellular and behavioral effects of drugs of abuse remain essentially unknown. Epac is known to regulate AMPA receptor (AMPAR) trafficking. Previous studies have shown that a single cocaine exposure in vivo leads to an increase in GluA2-lacking AMPARs in dopamine neurons of the ventral tegmental area (VTA)...
April 27, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27101990/disrupted-dynamics-of-f-actin-and-insulin-granule-fusion-in-ins-1-832-13-beta-cells-exposed-to-glucotoxicity-partial-restoration-by-glucagon-like-peptide-1
#13
Aurore Quinault, Blandine Gausseres, Danielle Bailbe, Nella Chebbah, Bernard Portha, Jamileh Movassat, Cecile Tourrel-Cuzin
Actin dynamics in pancreatic β-cells is involved in insulin exocytosis but the molecular mechanisms of this dynamics and its role in biphasic insulin secretion in pancreatic β-cells is largely unknown. Moreover, the impact of a glucotoxic environment on the sub-cortical actin network dynamics is poorly studied. In this study, we investigate the behavior of insulin granules and the subcortical actin network dynamics in INS-1 832/13 β-cells submitted to a normal or glucotoxic environment. Our results show that glucose stimulation leads to a reorganization of the subcortical actin network with a rupture of its interactions with t-SNARE proteins (Syntaxin 1A and SNAP-25), promoting insulin secretion in INS-1 832/13 β-cells...
August 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27100892/a-cardiac-mitochondrial-camp-signaling-pathway-regulates-calcium-accumulation-permeability-transition-and-cell-death
#14
Z Wang, D Liu, A Varin, V Nicolas, D Courilleau, P Mateo, C Caubere, P Rouet, A-M Gomez, G Vandecasteele, R Fischmeister, C Brenner
Although cardiac cytosolic cyclic 3',5'-adenosine monophosphate (cAMP) regulates multiple processes, such as beating, contractility, metabolism and apoptosis, little is known yet on the role of this second messenger within cardiac mitochondria. Using cellular and subcellular approaches, we demonstrate here the local expression of several actors of cAMP signaling within cardiac mitochondria, namely a truncated form of soluble AC (sACt) and the exchange protein directly activated by cAMP 1 (Epac1), and show a protective role for sACt against cell death, apoptosis as well as necrosis in primary cardiomyocytes...
2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27096875/increased-microvascular-permeability-in-mice-lacking-epac1-rapgef3
#15
R K Kopperud, C Brekke Rygh, T V Karlsen, C Krakstad, R Kleppe, E A Hoivik, M Bakke, O Tenstad, F Selheim, Å Lidén, L Madsen, T Pavlin, T Taxt, K Kristiansen, F-R E Curry, R K Reed, S O Døskeland
AIM: Maintenance of the blood and extracellular volume requires tight control of endothelial macromolecule permeability, which is regulated by cAMP signalling. 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 basal conditions. METHODS: Epac1(-/-) and Epac2(-/-) C57BL/6J mice were produced and compared with wild-type mice for transvascular flux of radio-labelled albumin in skin, adipose tissue, intestine, heart and skeletal muscle...
April 20, 2016: Acta Physiologica
https://www.readbyqxmd.com/read/26963850/epac-protein-kinase-c-alpha-signaling-in-purinergic-p2x3r-mediated-hyperalgesia-after-inflammation
#16
Yanping Gu, Guangwen Li, Yong Chen, Li-Yen Mae Huang
Sensitization of purinergic P2X3 receptors (P2X3Rs) is a major mechanism contributing to injury-induced exaggerated pain responses. We showed in a previous study that cyclic adenosine monophosphate (cAMP)-dependent guanine nucleotide exchange factor 1 (Epac1) in rat sensory dorsal root ganglia (DRGs) is upregulated after inflammatory injury, and it plays a critical role in P2X3R sensitization by activating protein kinase C epsilon (PKCε) inside the cells. protein kinase C epsilon has been established as the major PKC isoform mediating injury-induced hyperalgesic responses...
July 2016: Pain
https://www.readbyqxmd.com/read/26941424/cyclic-amp-sensor-epac-proteins-and-their-role-in-cardiovascular-function-and-disease
#17
REVIEW
Frank Lezoualc'h, Loubina Fazal, Marion Laudette, Caroline Conte
cAMP is a universal second messenger that plays central roles in cardiovascular regulation influencing gene expression, cell morphology, and function. A crucial step toward a better understanding of cAMP signaling came 18 years ago with the discovery of the exchange protein directly activated by cAMP (EPAC). The 2 EPAC isoforms, EPAC1 and EPAC2, are guanine-nucleotide exchange factors for the Ras-like GTPases, Rap1 and Rap2, which they activate independently of the classical effector of cAMP, protein kinase A...
March 4, 2016: Circulation Research
https://www.readbyqxmd.com/read/26854595/epac-activation-inhibits-acetaldehyde-induced-activation-and-proliferation-of-hepatic-stellate-cell-via-rap1
#18
Yan Yang, Feng Yang, Xiaojuan Wu, Xiongwen Lv, Jun Li
Hepatic stellate cells (HSCs) activation represents an essential event during alcoholic liver fibrosis (ALF). Previous studies have demonstrated that the rat HSCs could be significantly activated after exposure to 200 μmol/L acetaldehyde for 48 h, and the cAMP/PKA signaling pathways were also dramatically upregulated in activated HSCs isolated from alcoholic fibrotic rat liver. Exchange protein activated by cAMP (EPAC) is a family of guanine nucleotide exchange factors (GEFs) for the small Ras-like GTPases Rap, and is being considered as a vital mediator of cAMP signaling in parallel with the principal cAMP target protein kinase A (PKA)...
May 2016: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/26851245/calmodulin-kinase-ii-inhibition-limits-the-pro-arrhythmic-ca2-waves-induced-by-camp-phosphodiesterase-inhibitors
#19
Pierre Bobin, Audrey Varin, Florence Lefebvre, Rodolphe Fischmeister, Grégoire Vandecasteele, Jérôme Leroy
AIMS: A major concern of using phosphodiesterase (PDE) inhibitors in heart failure is their potential to increase mortality by inducing arrhythmias. By diminishing cyclic adenosine monophosphate (cAMP) hydrolysis, they promote protein kinase A (PKA) activity under β-adrenergic receptor (β-AR) stimulation, hence enhancing Ca(2+) cycling and contraction. Yet, cAMP also activates CaMKII via PKA or the exchange protein Epac, but it remains unknown whether these pathways are involved in the pro-arrhythmic effect of PDE inhibitors...
May 1, 2016: Cardiovascular Research
https://www.readbyqxmd.com/read/26840743/urocortin-1-mediated-cardioprotection-involves-xiap-and-cd40-ligand-recovery-role-of-epac2-and-erk1-2
#20
Eva Calderón-Sánchez, Ignacio Díaz, Antonio Ordóñez, Tarik Smani
AIMS: Urocortin-1 (Ucn-1) is an endogenous peptide that protects heart from ischemia and reperfusion (I/R) injuries. Ucn-1 is known to prevent cardiac cell death, but its role in the transcription of specific genes related to survival signaling pathway has not been fully defined. The aim of this study was to investigate the molecular signaling implicated in the improvement of cardiac myocytes survival induced by Ucn-1. METHODS AND RESULTS: Ucn-1 administration before ischemia and at the onset of reperfusion, in rat hearts perfused in Langendorff system, fully recovered heart contractility and other hemodynamic parameters...
2016: PloS One
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