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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
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
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
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
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
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
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
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
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
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
Reidun K Kopperud, Cecilie B Rygh, Tine V Karlsen, Camilla Krakstad, Rune Kleppe, Erling A Høivik, Marit Bakke, Olav Tenstad, Frode Selheim, Åsa Lidén, Lise Madsen, Tina Pavlin, Torfinn Taxt, Karsten Kristiansen, Fitz-Roy E Curry, Rolf K Reed, Stein O Døskeland
AIM: Maintenance of the blood and extracellular volume requires tight control of endothelial macromolecule permeability, which is regulated by cAMP signaling. The present 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 radiolabeled albumin in skin, adipose tissue, intestine, heart and skeletal muscle...
April 20, 2016: Acta Physiologica
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
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
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
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
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
Hyunhyo Seo, Kyungmin Lee
Astrocytes play a critical role in normal brain functions and maintaining the brain microenvironment, and defects in astrocytogenesis during neurodevelopment could give rise to severe mental illness and psychiatric disorders. During neuro-embryogenesis, astrocytogenesis involves astrocytic differentiation of neural precursor cells (NPCs) induced by signals from ciliary neurotrophic factor (CNTF) or pituitary adenylate cyclase-activating peptide (PACAP). However, in contrast to the CNTF signaling pathway, the exact mechanism underlying astrocytic differentiation induced by PACAP is unknown...
February 2016: BMB Reports
M Nenquin, J-C Henquin
Amplification of insulin secretion by cyclic AMP involves activation of protein kinase A (PKA) and Epac2 in pancreatic β cells. Recent hypotheses suggest that sulphonylurea receptor-1 (SUR1), the regulatory subunit of ATP-sensitive potassium channels, is implicated in Epac2 effects and that direct activation of Epac2 by hypoglycaemic sulphonylureas contributes to the stimulation of insulin secretion by these drugs. In the present experiments, using islets from Sur1KO mice, we show that dibutyryl-cAMP and membrane-permeant selective activators of Epac or PKA normally amplify insulin secretion in β cells lacking SUR1...
July 2016: Diabetes, Obesity & Metabolism
Sheng-Yu Wang, Michelle R Freeman, Venkatachalem Sathish, Michael A Thompson, Christina M Pabelick, Y S Prakash
Brain derived neurotropic factor (BDNF) is emerging as an important player in airway inflammation, remodeling, and hyperreactivity. Separately, there is increasing evidence that sex hormones contribute to pathophysiology in the lung. BDNF and sex steroid signaling are thought to be intricately linked in the brain. There is currently little information on BDNF and sex steroid interactions in the airway but is relevant to understanding growth factor signaling in the context of asthma in men versus women. In this study, we assessed the effect of sex steroids on BDNF expression and secretion in human airway smooth muscle (ASM)...
July 2016: Journal of Cellular Physiology
Evan P S Pratt, Amy E Salyer, Marcy L Guerra, Gregory H Hockerman
We previously reported that INS-1 cells expressing the intracellular II-III loop of the L-type Ca(2+) channel Cav1.2 (Cav1.2/II-III cells) are deficient in Ca(2+)-induced Ca(2+) release (CICR). Here we show that glucose-stimulated ERK 1/2 phosphorylation (GSEP) is slowed and reduced in Cav1.2/II-III cells compared to INS-1 cells. This parallels a decrease in glucose-stimulated cAMP accumulation (GS-cAMP) in Cav1.2/II-III cells. Influx of Ca(2+) via L-type Ca(2+) channels and CICR play roles in both GSEP and GS-cAMP in INS-1 cells since both are inhibited by nicardipine or ryanodine...
January 5, 2016: Molecular and Cellular Endocrinology
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