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https://www.readbyqxmd.com/read/28103481/motor-learning-requires-purkinje-cell-synaptic-potentiation-through-activation-of-ampa-receptor-subunit-glua3
#1
Nicolas Gutierrez-Castellanos, Carla M Da Silva-Matos, Kuikui Zhou, Cathrin B Canto, Maria C Renner, Linda M C Koene, Ozgecan Ozyildirim, Rolf Sprengel, Helmut W Kessels, Chris I De Zeeuw
Accumulating evidence indicates that cerebellar long-term potentiation (LTP) is necessary for procedural learning. However, little is known about its underlying molecular mechanisms. Whereas AMPA receptor (AMPAR) subunit rules for synaptic plasticity have been extensively studied in relation to declarative learning, it is unclear whether these rules apply to cerebellum-dependent motor learning. Here we show that LTP at the parallel-fiber-to-Purkinje-cell synapse and adaptation of the vestibulo-ocular reflex depend not on GluA1- but on GluA3-containing AMPARs...
January 18, 2017: Neuron
https://www.readbyqxmd.com/read/28071786/functional-and-cardioprotective-effects-of-simultaneous-and-individual-activation-of-protein-kinase-a-and-epac
#2
Igor Khaliulin, Mark Bond, Andrew F James, Zara Dyar, Raheleh Amini, Jason L Johnson, M-Saadeh Suleiman
BACKGROUND AND PURPOSE: Myocardial cAMP elevation confers cardioprotection against ischaemia/reperfusion (I/R) injury. cAMP activates two independent signalling pathways, PKA and Epac. This study investigated the cardiac effects of activating PKA and/or Epac and their involvement in cardioprotection against I/R. EXPERIMENTAL APPROACH: Hearts extracted from male rats were used either for determination of PKA and PKC activation or perfused in the Langendorff mode for either cardiomyocytes isolation or used to monitor functional activity at basal levels and after 30 min global ischaemia and 2 h reperfusion...
January 10, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28039940/epac-rap1-activated-mesenchymal-stem-cells-improve-cardiac-function%C3%A2-in-rat-model-of-myocardial-infarction
#3
Irfan Khan, Anwar Ali, Muhammad Aleem Akhter, Nadia Naeem, Maqsood Ahmed Chotani, Hana'a Iqbal, Nurul Kabir, Mehnaz Atiq, Asmat Salim
INTRODUCTION: Rap1, a member of Ras superfamily of small GTP-binding proteins, is involved in cardiovascular biology in numerous ways. It is an evolutionary conserved regulator of adhesion, polarity, differentiation and growth. AIMS: Our aim was to analyze Rap1 activated rat bone marrow mesenchymal stem cells (MSCs) for their potential role in adhesion and cardiac differentiation. METHODS: Myocardial infarction (MI) was produced in Sprague Dawley (SD) rats through occlusion of the left anterior descending coronary artery...
December 31, 2016: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/28039302/camp-signaling-of-adenylate-cyclase-toxin-blocks-the-oxidative-burst-of-neutrophils-through-epac-mediated-inhibition-of-phospholipase-c-activity
#4
Ondrej Cerny, Karen E Anderson, Len R Stephens, Phillip T Hawkins, Peter Sebo
The adenylate cyclase toxin-hemolysin (CyaA) plays a key role in immune evasion and virulence of the whooping cough agent Bordetella pertussis. CyaA penetrates the complement receptor 3-expressing phagocytes and ablates their bactericidal capacities by catalyzing unregulated conversion of cytosolic ATP to the key second messenger molecule cAMP. We show that signaling of CyaA-generated cAMP blocks the oxidative burst capacity of neutrophils by two converging mechanisms. One involves cAMP/protein kinase A-mediated activation of the Src homology region 2 domain-containing phosphatase-1 (SHP-1) and limits the activation of MAPK ERK and p38 that are required for assembly of the NADPH oxidase complex...
December 30, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27995459/epac-activation-inhibits-il-6-induced-cardiac-myocyte-dysfunction
#5
Huiling Jin, Takayuki Fujita, Meihua Jin, Reiko Kurotani, Yuko Hidaka, Wenqian Cai, Kenji Suita, Rajesh Prajapati, Chen Liang, Yoshiki Ohnuki, Yasumasa Mototani, Masanari Umemura, Utako Yokoyama, Motohiko Sato, Satoshi Okumura, Yoshihiro Ishikawa
Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic and thus catecholamine signaling is activated thereafter to compensate for cardiac dysfunction. The mechanism of such compensation by catecholamine signaling has been traditionally understood to be cyclic AMP-dependent protein kinase (PKA)-mediated enforcement of cardiac contractility. We hypothesized that the exchange protein activated by cAMP (Epac), a newly identified target of cAMP signaling that functions independently of PKA, also plays a key role in this mechanism...
December 19, 2016: Journal of Physiological Sciences: JPS
https://www.readbyqxmd.com/read/27989572/the-role-of-camp-and-its-downstream-targets-in-neurite-growth-in-the-adult-nervous-system
#6
REVIEW
Nicholas J Batty, Keith K Fenrich, Karim Fouad
Injured neurons in the adult mammalian central nervous system (CNS) have a very limited capacity for axonal regeneration and neurite outgrowth. This inability to grow new axons or to regrow injured axons is due to the presence of molecules that inhibit axonal growth, and age related changes in the neuron's innate growth capabilities. Available levels of cAMP are thought to have an important role in linking both of these factors. Elevated levels of cAMP in the developing nervous system are important for the guidance and stability of growth cones...
December 15, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/27984207/acquired-exchange-protein-directly-activated-by-cyclic-adenosine-monophosphate-activity-induced-by-p38-mitogen-activated-protein-kinase-in-primary-afferent-neurons-contributes-to-sustaining-postincisional-nociception
#7
Megumi Matsuda, Kentaro Oh-Hashi, Isao Yokota, Teiji Sawa, Fumimasa Amaya
BACKGROUND: The molecular mechanisms responsible for sustained pain after tissue injury are largely unknown. The aim of this study was to clarify the role of exchange protein directly activated by cyclic adenosine monophosphate (EPAC) in sustained postincisional nociception, using tissue injury-induced nociceptor priming, and involvement of p38 mitogen-activated protein kinase (p38MAPK) in EPAC-mediated nociceptor priming. METHODS: Plantar incisions were made in the hind paws of Sprague-Dawley rats (n = 144)...
January 2017: Anesthesiology
https://www.readbyqxmd.com/read/27984073/host-epac1-is-required-for-camp-mediated-invasion-by-trypanosoma-cruzi
#8
Daniel Musikant, Gabriel Ferri, Ignacio M Durante, Carlos A Buscaglia, Daniel L Altschuler, Martin M Edreira
Mechanistic details of the modulation by cAMP of Trypanosoma cruzi host cell invasion remain ill-defined. Here we report that activation of host's Epac1 stimulated invasion, whereas specific pharmacological inhibition or maneuvers that alter Epac1 subcellular localization significantly reduced invasion. Furthermore, while specific activation of host cell PKA showed no effect, its inhibition resulted in an increased invasion, revealing a crosstalk between the PKA and Epac signaling pathways during the process of invasion...
January 2017: Molecular and Biochemical Parasitology
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
#9
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/27908835/modulation-of-signaling-through-gpcr-camp-pka-pathways-by-pde4-depends-on-stimulus-intensity-possible-implications-for-the-pathogenesis-of-acrodysostosis-without-hormone-resistance
#10
Emmanuelle Motte, Catherine Le Stunff, Claire Briet, Nicolas Dumaz, Caroline Silve
In acrodysostosis without hormone resistance, a disease caused by phosphodiesterase (PDE)-4D mutations, increased PDE activity leads to bone developmental defects but with normal renal responses to PTH. To identify potential mechanisms for these disparate responses, we compared the effect of PDE activity on hormone signaling through the GPCR-Gsα-cAMP-PKA pathway in cells from two lineages, HEK-293 cells stably overexpressing PTH1R (HEKpthr) and human dermal fibroblasts, including studies evaluating cAMP levels using an Epac-based BRET-sensor for cAMP (CAMYEL)...
November 28, 2016: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27900608/interaction-of-epac-with-non-canonical-cyclic-nucleotides
#11
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/27894809/cyclic-amp-camp-confers-drug-resistance-against-dna-damaging-agents-via-pkaia-in-cml-cells
#12
Ling-Yi Xiao, Wai-Ming Kan
Cyclic adenosine monophosphate (cAMP) regulates many vital functions such as metabolism, proliferation, differentiation and death. Depending on cell types and stimulators, cAMP could either promote or attenuate cell death. cAMP signal can be transduced by protein kinase A (PKA) and/or exchange protein directly activated by cAMP (EPAC). In CML cells, cAMP may suppress their proliferation and enhance their differentiation. However, the role of cAMP on DNA damaging agent toxicity and the mechanism involved has not been studied...
January 5, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27867203/epac2a-null-mice-exhibit-obesity-prone-nature-more-susceptible-to-leptin-resistance
#13
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...
December 13, 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/27830723/inhibition-of-epac1-suppresses-mitochondrial-fission-and-reduces-neointima-formation-induced-by-vascular-injury
#14
Hui Wang, William G Robichaux, Ziqing Wang, Fang C Mei, Ming Cai, Guangwei Du, Ju Chen, Xiaodong Cheng
Vascular smooth muscle cell (VSMC) activation in response to injury plays an important role in the development of vascular proliferative diseases, including restenosis and atherosclerosis. The aims of this study were to ascertain the physiological functions of exchange proteins directly activated by cAMP isoform 1 (Epac1) in VSMC and to evaluate the potential of Epac1 as therapeutic targets for neointima formation during vascular remodeling. In a mouse carotid artery ligation model, genetic knockdown of the Epac1 gene led to a significant reduction in neointima obstruction in response to vascular injury...
November 10, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27789473/kv7-channel-activation-underpins-epac-dependent-relaxations-of-rat-arteries
#15
Jennifer B Stott, Vincenzo Barrese, Iain A Greenwood
OBJECTIVE: To establish the role of Kv7 channels in EPAC (exchange protein directly activated by cAMP)-dependent relaxations of the rat vasculature and to investigate whether this contributes to β-adrenoceptor-mediated vasorelaxations. APPROACH AND RESULTS: Isolated rat renal and mesenteric arteries (RA and MA, respectively) were used for isometric tension recording to study the relaxant effects of a specific EPAC activator and the β-adrenoceptor agonist isoproterenol in the presence of potassium channel inhibitors and cell signaling modulators...
October 27, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/27715254/the-angiotensin-1-7-mas-axis-improves-pancreatic-%C3%AE-cell-function-in-vitro-and-in-vivo
#16
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 angiotensin-converting enzyme 2/angiotensin (Ang)-(1-7)/Mas axis of the renin-angiotensin system often opposes the detrimental effects of the angiotensin-converting enzyme/Ang II/Ang II type 1 receptor axis and has been associated with beneficial effects on glucose homeostasis, whereas 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...
December 2016: Endocrinology
https://www.readbyqxmd.com/read/27709364/%C3%AE-adrenergic-modulation-of-cancer-cell-proliferation-available-evidence-and-clinical-perspectives
#17
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
https://www.readbyqxmd.com/read/27673556/cyclic-amp-effectors-regulate-myometrial-oxytocin-receptor-expression
#18
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
https://www.readbyqxmd.com/read/27663700/divergent-camp-signaling-differentially-regulates-serotonin-induced-spinal-motor-plasticity
#19
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...
February 2017: Neuropharmacology
https://www.readbyqxmd.com/read/27649969/epac2-rap1-signaling-regulates-reactive-oxygen-species-production-and-susceptibility-to-cardiac-arrhythmias
#20
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
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