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Anika Sahr, Carmen Wolke, Jonas Maczewsky, Peter Krippeit-Drews, Anja Tetzner, Gisela Drews, Simone Venz, Sarah Gürtler, Jens van den Brandt, Sabine Berg, Paula Döring, Frank Dombrowski, Thomas Walther, Uwe Lendeckel
The ACE2/angiotensin (Ang)-(1-7)/Mas axis of the renin-angiotensin system (RAS) often opposes the detrimental effects of the ACE/AngII/AT1 axis and has been associated with beneficial effects on glucose homeostasis, while underlying mechanisms are mostly unknown. Here, we investigate the effects of Ang-(1-7) and its receptor Mas on β-cell function. Isolated islets from Mas-deficient and wild-type mice were stimulated with Ang-(1-7) or its antagonists and effects on insulin secretion determined. Islets' cytoplasmic calcium and cAMP concentrations, mRNA amounts of Ins1, Ins2, Pdx1, and Mafa, and effects of inhibitors of cAMP downstream signaling were determined...
October 7, 2016: Endocrinology
Marisa Coelho, Cátia Soares-Silva, Daniela Brandão, Franca Marino, Marco Cosentino, Laura Ribeiro
PURPOSE: In this review, we aimed to present and discuss the available preclinical and epidemiological evidences regarding the modulation of cancer cell proliferation by β-adrenoceptors (β-AR), with a specific focus on the putative effects of β-blockers according to their pharmacological properties. METHODS: A comprehensive review of the published literature was conducted, and the evidences concerning the involvement of β-AR in cancer as well as the possible role of β-blockers were selected and discussed...
October 5, 2016: Journal of Cancer Research and Clinical Oncology
Angela Yulia, Natasha Singh, Kaiyu Lei, Suren R Sooranna, Mark R Johnson
The factors that initiate human labor are poorly understood. We have tested the hypothesis that a decline in cAMP/PKA function leads to the onset of labor. Initially, we identified myometrial cAMP/PKA responsive genes (6 up-regulated and 5 down-regulated genes) and assessed their expression in myometrial samples taken from different stages of pregnancy and labor. We found that the oxytocin receptor (OTR) was one of the cAMP repressed genes and, given the importance of OTR in the labor process, we studied the mechanisms involved in greater detail using siRNA, chemical agonists and antagonists of the cAMP effectors...
September 27, 2016: Endocrinology
D P Fields, G S Mitchell
Spinal metabotropic serotonin receptors encode transient experiences into long-lasting changes in motor behavior (i.e. motor plasticity). While interactions between serotonin receptor subtypes are known to regulate plasticity, the significance of molecular divergence in downstream G protein coupled receptor signaling is not well understood. Here we tested the hypothesis that distinct cAMP dependent signaling pathways differentially regulate serotonin-induced phrenic motor facilitation (pMF); a well-studied model of spinal motor plasticity...
September 20, 2016: Neuropharmacology
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
George D Bittner, Christopher S Spaeth, Andrew D Poon, Zachary S Burgess, Christopher H McGill
The repair (sealing) of plasmalemmal damage, consisting of small holes to complete transections, is critical for cell survival, especially for neurons that rarely regenerate cell bodies. We first describe and evaluate different measures of cell sealing. Some measures, including morphological/ultra-structural observations, membrane potential, and input resistance, provide very ambiguous assessments of plasmalemmal sealing. In contrast, measures of ionic current flow and dye barriers can, if appropriately used, provide more accurate assessments...
July 2016: Neural Regeneration Research
Evi Glas, Harald Mückter, Thomas Gudermann, Andreas Breit
Gs protein-coupled receptors regulate many vital body functions by activation of cAMP response elements (CRE) via cAMP-dependent kinase A (PKA)-mediated phosphorylation of the CRE binding protein (CREB). Melanocortin 4 receptors (MC4R) are prototypical Gs-coupled receptors that orchestrate the hypothalamic control of food-intake and metabolism. Remarkably, the significance of PKA for MC4R-induced CRE-dependent transcription in hypothalamic cells has not been rigorously interrogated yet. In two hypothalamic cell lines, we observed that blocking PKA activity had only weak or no effects on reporter gene expression...
2016: Scientific Reports
Peter V DiStefano, Alan V Smrcka, Angela J Glading
The phosphoinositide-specific phospholipase C, PLCε, is a unique signaling protein with known roles in regulating cardiac myocyte growth, astrocyte inflammatory signaling, and tumor formation. PLCε is also expressed in endothelial cells, however its role in endothelial regulation is not fully established. We show that endothelial cells of multiple origins, including human pulmonary artery (HPAEC), human umbilical vein (HUVEC), and immortalized brain microvascular (hCMEC/D3) endothelial cells, express PLCε...
2016: PloS One
Walter Miklos, Petra Heffeter, Christine Pirker, Sonja Hager, Christian R Kowol, Sushilla van Schoonhoven, Mirjana Stojanovic, Bernhard K Keppler, Walter Berger
Triapine, an anticancer thiosemicarbazone, is currently under clinical investigation. Whereas promising results were obtained in hematological diseases, trials in solid tumors widely failed. To understand mechanisms causing triapine insensitivity, we have analysed genomic alterations in a triapine-resistant SW480 subline (SW480/tria). Only one distinct genomic loss was observed specifically in SW480/tria cells affecting the phosphodiesterase 4D (PDE4D) gene locus. Accordingly, pharmacological inhibition of PDE4D resulted in significant triapine resistance in SW480 cells...
September 2, 2016: Oncotarget
D Avanzato, T Genova, A Fiorio Pla, M Bernardini, S Bianco, B Bussolati, D Mancardi, E Giraudo, F Maione, P Cassoni, I Castellano, L Munaron
Purinergic signaling is involved in inflammation and cancer. Extracellular ATP accumulates in tumor interstitium, reaching hundreds micromolar concentrations, but its functional role on tumor vasculature and endothelium is unknown. Here we show that high ATP doses (>20 μM) strongly inhibit migration of endothelial cells from human breast carcinoma (BTEC), but not of normal human microvascular EC. Lower doses (1-10 mm result ineffective. The anti-migratory activity is associated with cytoskeleton remodeling and is significantly prevented by hypoxia...
2016: Scientific Reports
Jada C Domingue, Mei Ao, Jayashree Sarathy, Mrinalini C Rao
Bile acids are known to initiate intricate signaling events in a variety of tissues, primarily in the liver and gastrointestinal tract. Of the known bile acids, only the dihydroxy species, deoxycholic acid and chenodeoxycholic acid (CDCA), and their conjugates, activate processes that stimulate epithelial Cl(-) secretion. We have previously published that CDCA acts in a rapid manner to stimulate colonic ion secretion via protein kinase A (PKA)-mediated activation of the dominant Cl(-) channel, the cystic fibrosis transmembrane conductance regulator (CFTR) (AJP 305:C447-56, 2013); however, PKA signaling did not account for the entire CDCA response...
August 24, 2016: American Journal of Physiology. Cell Physiology
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
Serge Goupil, Loïze Maréchal, Hassan El Hajj, Marie-Ève Tremblay, François J Richard, Pierre Leclerc
In mammals, adenosine 3', 5'-cyclic monophosphate (cAMP) is known to play highly important roles in sperm motility and acrosomal exocytosis. It is known to act through protein phosphorylation via PRKA and through the activation of guanine nucleotide exchange factors like EPAC. Sperm intracellular cAMP levels depend on the activity of adenylyl cyclases, mostly SACY, though transmembrane-containing adenylyl cyclases are also present, and on the activity of cyclic nucleotide phosphodiesterases (PDE) whose role is to degrade cAMP into 5'-AMP...
2016: PloS One
Jeong Ah Lim, Yong-Sung Juhnn
Stress conditions are correlated with tumor growth, progression and metastasis. We hypothesized that stress signals might affect tumor progression via epigenetic control of gene expression and investigated the effects of stress signals on the expression levels of histone deacetylases (HDACs) and the underlying mechanisms of these effects in lung cancer cells. Treatment with isoproterenol (ISO), an analog of the stress signal epinephrine, increased the expression of HDAC6 protein and mRNA in H1299 lung cancer cells...
2016: Experimental & Molecular Medicine
Hossein Mostafavi, Mojtaba Khaksarian, Mohammad Taghi Joghataei, Sadegh Yoosefee, Maryam Soleimannejad, Raheleh Gholamzadeh, Sanam Seifollahi Bahnamiri, Mahmoud Reza Hadjighassem
INTRODUCTION: Malignant astrocytic gliomas are the most common and lethal brain malignancies due to their refractory to the current therapies. Nowadays, molecular targeted therapy has attracted great attention in treatment of glioma. Connexin 43 (Cx43) and micro ribonucleic acid-21(miR-21) are among molecules that are involved in glioma development and progression. These molecules showed potential to be as target molecules with regard to glioma. Some studies have reported that cyclic adenosine monophosphate (cAMP) signaling could be effective on Cx43 and miR-21 in tissues other than in brain...
January 2015: Basic and Clinical Neuroscience
Thomas Brand, Kar Lai Poon, Subreena Simrick, Roland F R Schindler
3'-5'-cyclic adenosine monophosphate (cAMP) is a second messenger, which plays an important role in the heart. It is generated in response to activation of G-protein-coupled receptors (GPCRs). Initially, it was thought that protein kinase A (PKA) exclusively mediates cAMP-induced cellular responses such as an increase in cardiac contractility, relaxation, and heart rate. With the identification of the exchange factor directly activated by cAMP (EPAC) and hyperpolarizing cyclic nucleotide-gated (HCN) channels as cAMP effector proteins it became clear that a protein network is involved in cAMP signaling...
May 21, 2014: Journal of Cardiovascular Development and Disease
Yanping Gu, Congying Wang, Guangwen Li, Li-Yen Mae Huang
Sensitization of purinergic P2X3 receptors (P2X3Rs) contributes to the production of exaggerated nociceptive responses following inflammatory injury. We showed previously that prostaglandin E2 (PGE2) potentiates P2X3R-mediated ATP currents in dorsal root ganglion neurons isolated from both control and complete Freund’s adjuvant-induced inflamed rats. PGE2 potentiation of ATP currents depends only on PKA signaling in control neurons, but it depends on both PKA and PKC signaling in inflamed neurons. We further found that inflammation evokes an increase in exchange proteins directly activated by cAMP (Epacs) in dorsal root ganglions...
2016: Molecular Pain
Yaohua Hu, William G Robichaux, Fang C Mei, Eun Ran Kim, Hui Wang, Qingchun Tong, Jianping Jin, Mingxuan Xu, Ju Chen, Xiaodong Cheng
Epacs (exchange proteins directly activated by cyclic AMP [cAMP]) act as downstream effectors of cAMP and play important roles in energy balance and glucose homeostasis. While global deletion of Epac1 in mice leads to heightened leptin sensitivity in the hypothalamus and partial protection against high-fat diet (HFD)-induced obesity, the physiological functions of Epac1 in white adipose tissue (WAT) has not been explored. Here, we report that adipose tissue-specific Epac1 knockout (AEKO) mice are more prone to HFD-induced obesity, with increased food intake, reduced energy expenditure, and impaired glucose tolerance...
October 1, 2016: Molecular and Cellular Biology
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
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