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https://www.readbyqxmd.com/read/28317879/a-novel-method-for-screening-adenosine-receptor-specific-agonists-for-use-in-adenosine-drug-development
#1
Karlie R Jones, Uimook Choi, Ji-Liang Gao, Robert D Thompson, Larry E Rodman, Harry L Malech, Elizabeth M Kang
Agonists that target the A1, A2A, A2B and A3 adenosine receptors have potential to be potent treatment options for a number of diseases, including autoimmune diseases, cardiovascular disease and cancer. Because each of these adenosine receptors plays a distinct role throughout the body, obtaining highly specific receptor agonists is essential. Of these receptors, the adenosine A2AR and A2BR share many sequence and structural similarities but highly differ in their responses to inflammatory stimuli. Our laboratory, using a combination of specially developed cell lines and calcium release analysis hardware, has created a new and faster method for determining specificity of synthetic adenosine agonist compounds for the A2A and A2B receptors in human cells...
March 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28300546/cocaine-self-administration-specifically-increases-a2ar-d2r-and-d2r-sigma1r-heteroreceptor-complexes-in-the-rat-nucleus-accumbens-shell-relevance-for-cocaine-use-disorder
#2
Dasiel O Borroto-Escuela, Manuel Narváez, Karolina Wydra, Julia Pintsuk, Luca Pinton, Antonio Jimenez-Beristain, Michael Di Palma, Joanna Jastrzębska, Malgorzata Filip, Kjell Fuxe
Adenosine 2A receptor (A2AR) agonists were indicated to reduce cocaine reward and cocaine seeking mainly through activation of antagonistic allosteric A2AR-dopamine D2R (D2R) interactions in A2AR-D2R heteroreceptor complexes. Furthermore, it was shown that modulation of cocaine reward involves antagonistic A2AR-D2R interactions in the ventral but not the dorsal striatum in rats. In the current work the proximity ligation assay (PLA) was used to further study the A2AR-D2R heteroreceptor complexes in the nucleus accumbens shell and core as well as the dorsal striatum under the influence of cocaine self-administration in rats...
March 12, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28279185/constitutively-stressed-yeast-strains-are-high-yielding-for-recombinant-fps1-implications-for-the-translational-regulation-of-an-aquaporin
#3
Stephanie P Cartwright, Richard A J Darby, Debasmita Sarkar, Nicklas Bonander, Stephane R Gross, Mark P Ashe, Roslyn M Bill
BACKGROUND: We previously selected four strains of Saccharomyces cerevisiae for their ability to produce the aquaporin Fps1 in sufficient yield for further study. Yields from the yeast strains spt3Δ, srb5Δ, gcn5Δ and yTHCBMS1 (supplemented with 0.5 μg/mL doxycycline) that had been transformed with an expression plasmid containing 249 base pairs of 5' untranslated region (UTR) in addition to the primary FPS1 open reading frame (ORF) were 10-80 times higher than yields from wild-type cells expressing the same plasmid...
March 9, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/28270751/understanding-the-role-of-gpcr-heteroreceptor-complexes-in-modulating-the-brain-networks-in-health-and-disease
#4
REVIEW
Dasiel O Borroto-Escuela, Jens Carlsson, Patricia Ambrogini, Manuel Narváez, Karolina Wydra, Alexander O Tarakanov, Xiang Li, Carmelo Millón, Luca Ferraro, Riccardo Cuppini, Sergio Tanganelli, Fang Liu, Malgorzata Filip, Zaida Diaz-Cabiale, Kjell Fuxe
The introduction of allosteric receptor-receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes of the central nervous system (CNS) gave a new dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed to be based on the reorganization of the homo- and heteroreceptor complexes in the postjunctional membrane of synapses. Long-term memory may be created by the transformation of parts of the heteroreceptor complexes into unique transcription factors which can lead to the formation of specific adapter proteins...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28264466/synthesis-and-characterization-of-a-new-bivalent-ligand-combining-caffeine-and-docosahexaenoic-acid
#5
Víctor Fernández-Dueñas, Jhonny Azuaje, Xavier Morató, Begoña Cordobilla, Joan Carles Domingo, Eddy Sotelo, Francisco Ciruela
Caffeine is a promising drug for the management of neurodegenerative diseases such as Parkinson's disease (PD), demonstrating neuroprotective properties that have been attributed to its interaction with the basal ganglia adenosine A2A receptor (A2AR). However, the doses needed to exert these neuroprotective effects may be too high. Thus, it is important to design novel approaches that selectively deliver this natural compound to the desired target. Docosahexaenoic acid (DHA) is the major omega-3 fatty acid in the brain and can act as a specific carrier of caffeine...
February 27, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28263576/in-situ-reconstitution-of-the-adenosine-a2a-receptor-in-spontaneously-formed-synthetic-liposomes
#6
Roberto J Brea, Christian M Cole, Brent R Lyda, Libin Ye, R Scott Prosser, Roger K Sunahara, Neal K Devaraj
Cell transmembrane receptors play a key role in the detection of environmental stimuli and control of intracellular communication. G protein-coupled receptors constitute the largest transmembrane protein family involved in cell signaling. However, current methods for their functional reconstitution in biomimetic membranes remain both challenging and limited in scope. Herein, we describe the spontaneous reconstitution of adenosine A2A receptor (A2AR) during the de novo formation of synthetic liposomes via native chemical ligation...
March 15, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28239340/dopamine-induced-changes-in-g%C3%AE-olf-protein-levels-in-striatonigral-and-striatopallidal-medium-spiny-neurons-underlie-the-genesis-of-l-dopa-induced-dyskinesia-in-parkinsonian-mice
#7
Ryoma Morigaki, Shinya Okita, Satoshi Goto
The dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), exerts powerful therapeutic effects but eventually generates l-DOPA-induced dyskinesia (LID) in patients with Parkinson's disease (PD). LID has a close link with deregulation of striatal dopamine/cAMP signaling, which is integrated by medium spiny neurons (MSNs). Olfactory type G-protein α subunit (Gαolf), a stimulatory GTP-binding protein encoded by the GNAL gene, is highly concentrated in the striatum, where it positively couples with dopamine D1 (D1R) receptor and adenosine A2A receptor (A2AR) to increase intracellular cAMP levels in MSNs...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28235548/chronic-and-acute-adenosine-a2a-receptor-blockade-prevents-long-term-episodic-memory-disruption-caused-by-acute-cannabinoid-cb1-receptor-activation
#8
Francisco M Mouro, Vânia L Batalha, Diana G Ferreira, Joana E Coelho, Younis Baqi, Christa E Müller, Luísa V Lopes, Joaquim A Ribeiro, Ana M Sebastião
Cannabinoid-mediated memory impairment is a concern in cannabinoid-based therapies. Caffeine exacerbates cannabinoid CB1 receptor (CB1R)-induced memory deficits through an adenosine A1 receptor-mediated mechanism. We now evaluated how chronic or acute blockade of adenosine A2A receptors (A2ARs) affects long-term episodic memory deficits induced by a single injection of a selective CB1R agonist. Long-term episodic memory was assessed by the novel object recognition (NOR) test. Mice received an intraperitoneal (i...
February 21, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28220900/membrane-cholesterol-access-into-a-g-protein-coupled-receptor
#9
Ramon Guixà-González, José L Albasanz, Ismael Rodriguez-Espigares, Manuel Pastor, Ferran Sanz, Maria Martí-Solano, Moutusi Manna, Hector Martinez-Seara, Peter W Hildebrand, Mairena Martín, Jana Selent
Cholesterol is a key component of cell membranes with a proven modulatory role on the function and ligand-binding properties of G-protein-coupled receptors (GPCRs). Crystal structures of prototypical GPCRs such as the adenosine A2A receptor (A2AR) have confirmed that cholesterol finds stable binding sites at the receptor surface suggesting an allosteric role of this lipid. Here we combine experimental and computational approaches to show that cholesterol can spontaneously enter the A2AR-binding pocket from the membrane milieu using the same portal gate previously suggested for opsin ligands...
February 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28193701/osteoblastic-lrp4-promotes-osteoclastogenesis-by-regulating-atp-release-and-adenosine-a2ar-signaling
#10
Lei Xiong, Ji-Ung Jung, Hao-Han Guo, Jin-Xiu Pan, Xiang-Dong Sun, Lin Mei, Wen-Cheng Xiong
Bone homeostasis depends on the functional balance of osteoblasts (OBs) and osteoclasts (OCs). Lrp4 is a transmembrane protein that is mutated in patients with high bone mass. Loss of Lrp4 in OB-lineage cells increases bone mass by elevating bone formation by OBs and reducing bone resorption by OCs. However, it is unclear how Lrp4 deficiency in OBs impairs osteoclastogenesis. Here, we provide evidence that loss of Lrp4 in the OB lineage stabilizes the prorenin receptor (PRR) and increases PRR/V-ATPase-driven ATP release, thereby enhancing the production of the ATP derivative adenosine...
March 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28179537/early-tyrosine-phosphorylation-events-following-adenosine-a2a-receptor-in-human-neutrophils-identification-of-regulated-pathways
#11
Miriam S Giambelluca, Marc Pouliot
Activation of the adenosine 2A receptor (A2AR) elevates intracellular levels of cAMP and acts as a physiologic inhibitor of inflammatory neutrophil functions. In this study, we looked into the impact of A2AR engagement on early phosphorylation events. Neutrophils were stimulated with well-characterized proinflammatory agonists in the absence or presence of an A2AR agonist {3-[4-[2-[ [6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino] ethyl] phenyl] propanoic acid (CGS 21680)}, PGE2, or a mixture of the compounds RO 20-1724 and forskolin...
February 8, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28167788/crystal-structure-of-the-adenosine-a2a-receptor-bound-to-an-antagonist-reveals-a-potential-allosteric-pocket
#12
Bingfa Sun, Priti Bachhawat, Matthew Ling-Hon Chu, Martyn Wood, Tom Ceska, Zara A Sands, Joel Mercier, Florence Lebon, Tong Sun Kobilka, Brian K Kobilka
The adenosine A2A receptor (A2AR) has long been implicated in cardiovascular disorders. As more selective A2AR ligands are being identified, its roles in other disorders, such as Parkinson's disease, are starting to emerge, and A2AR antagonists are important drug candidates for nondopaminergic anti-Parkinson treatment. Here we report the crystal structure of A2A receptor bound to compound 1 (Cmpd-1), a novel A2AR/N-methyl d-aspartate receptor subtype 2B (NR2B) dual antagonist and potential anti-Parkinson candidate compound, at 3...
February 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28165340/targeting-the-adenosine-2a-receptor-enhances-chimeric-antigen-receptor-t-cell-efficacy
#13
Paul A Beavis, Melissa A Henderson, Lauren Giuffrida, Jane K Mills, Kevin Sek, Ryan S Cross, Alexander J Davenport, Liza B John, Sherly Mardiana, Clare Y Slaney, Ricky W Johnstone, Joseph A Trapani, John Stagg, Sherene Loi, Lev Kats, David Gyorki, Michael H Kershaw, Phillip K Darcy
Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs)...
March 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28153452/adenosine-receptors-modulators-of-lipid-availability-that-are-controlled-by-lipid-levels
#14
REVIEW
Andrea Leiva, Enrique Guzmán-Gutiérrez, Susana Contreras-Duarte, Bárbara Fuenzalida, Claudette Cantin, Lorena Carvajal, Rocío Salsoso, Jaime Gutiérrez, Fabián Pardo, Luis Sobrevia
Adenosine as well as agonists and antagonists for the four adenosine receptor subtypes (A1R, A2AR, A2BR and A3R) play a role in several key physiological and pathophysiological processes, including the regulation of vascular tone, thrombosis, immune response, inflammation, and angiogenesis. This review focuses on the adenosine-mediated regulation of lipid availability in the cell and in the systemic circulation as well in humans and animal models. Therefore, adenosine, mainly by acting on A1R, inhibits lipolysis activity, leading to reduction of the circulating fatty acid levels...
January 30, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28130124/calcium-modulates-calmodulin-%C3%AE-actinin-1-interaction-with-and-agonist-dependent-internalization-of-the-adenosine-a2a-receptor
#15
Henni Piirainen, Jaume Taura, Petri Kursula, Francisco Ciruela, Veli-Pekka Jaakola
Adenosine receptors are G protein-coupled receptors that sense extracellular adenosine to transmit intracellular signals. One of the four adenosine receptor subtypes, the adenosine A2A receptor (A2AR), has an exceptionally long intracellular C terminus (A2AR-ct) that mediates interactions with a large array of proteins, including calmodulin and α-actinin. Here, we aimed to ascertain the α-actinin 1/calmodulin interplay whilst binding to A2AR and the role of Ca(2+) in this process. First, we studied the A2AR-α-actinin 1 interaction by means of native polyacrylamide gel electrophoresis, isothermal titration calorimetry, and surface plasmon resonance, using purified recombinant proteins...
April 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28120151/the-ying-and-yang-of-adenosine-a1-and-a2a-receptors-on-erk1-2-activation-in-a-rat-model-of-global-cerebral-ischemia-reperfusion-injury
#16
Reham M Atef, Azza M Agha, Abdel-Rahman A Abdel-Rhaman, Noha N Nassar
Adenosine impacts cerebral ischemia reperfusion (IR) through the inhibitory A1 and the excitatory A2 receptors. The present study aimed at investigating the contrasting role of pERK1/2 in mediating adenosine A1R (protective) versus A2AR (deleterious) effects in IR. Male Wistar rats subjected to bilateral carotid occlusion (45 min) followed by reperfusion (24 h) exhibited increased pERK1/2 activity, downstream from DAG pathway, along with increases in hippocampal glutamate, c-Fos, NF-κB, TNF-α, iNOS, TBARS, cytochrome c, caspase-3, BDNF, Nrf2, and IL-10 contents...
January 24, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28112177/adenosine-a2a-receptor-deficiency-attenuates-the-somnogenic-effect-of-prostaglandin-d2-in-mice
#17
Bin-Jia Zhang, Zhi-Li Huang, Jiang-Fan Chen, Yoshihiro Urade, Wei-Min Qu
Prostaglandin D2 (PGD2) is one of the most potent endogenous sleep promoting substances. PGD2 activates the PGD2 receptor (DPR) and increases the extracellular level of adenosine in wild-type (WT) mice but not DPR knockout (KO) mice, suggesting that PGD2-induced sleep is DPR-dependent, and adenosine may be the signaling molecule that mediates the somnogenic effect of PGD2. The aim of this study was to determine the involvement of the adenosine A2A receptor (A2AR) in PGD2-induced sleep.We infused PGD2 into the lateral ventricle of WT and A2AR KO mice between 20:00 and 2:00 for 6 h, and electroencephalograms and electromyograms were simultaneously recorded...
January 23, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28102227/singular-location-and-signaling-profile-of-adenosine-a2a-cannabinoid-cb1-receptor-heteromers-in-the-dorsal-striatum
#18
Estefanía Moreno, Anna Chiarlone, Mireia Medrano, Mar Puigdellívol, Lucka Bibic, Lesley A Howell, Eva Resel, Nagore Puente, María J Casarejos, Juan Perucho, Joaquín Botta, Nuria Suelves, Francisco Ciruela, Silvia Ginés, Ismael Galve-Roperh, Vicent Casadó, Pedro Grandes, Beat Lutz, Krisztina Monory, Enric I Canela, Carmen Lluís, Peter J McCormick, Manuel Guzmán
The dorsal striatum is a key node for many neurobiological processes such as motor activity, cognitive functions, and affective processes. The proper functioning of striatal neurons relies critically on metabotropic receptors. Specifically, the main adenosine and endocannabinoid receptors present in the striatum, ie, adenosine A2A receptor (A2AR) and cannabinoid CB1 receptor (CB1R), are of pivotal importance in the control of neuronal excitability. Facilitatory and inhibitory functional interactions between striatal A2AR and CB1R have been reported, and evidence supports that this cross-talk may rely, at least in part, on the formation of A2AR-CB1R heteromeric complexes...
January 19, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28088487/adenosine-receptors-and-caffeine-in-retinopathy-of-prematurity
#19
REVIEW
Jiang-Fan Chen, Shuya Zhang, Rong Zhou, Zhenlang Lin, Xiaohong Cai, Jing Lin, Yuqing Huo, Xiaoling Liu
Retinopathy of prematurity (ROP) is a major cause of childhood blindness in the world and is caused by oxygen-induced damage to the developing retinal vasculature, resulting in hyperoxia-induced vaso-obliteration and subsequent delayed retinal vascularization and hypoxia-induced pathological neovascularization driven by vascular endothelial growth factor (VEGF) signaling pathway in retina. Current anti-VEGF therapy has shown some effective in a clinical trial, but is associated with the unintended effects on delayed eye growth and retinal vasculature development of preterm infants...
January 11, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28062599/in-vivo-evaluation-of-11c-preladenant-for-pet-imaging-of-adenosine-a2a-receptors-in-the-conscious-monkey
#20
Xiaoyun Zhou, Ronald Boellaard, Kiichi Ishiwata, Muneyuki Sakata, Rudi A Dierckx, Johan de Jong, Shingo Nishiyama, Hiroyuki Ohba, Hideo Tsukada, Erik F de Vries, Philip H Elsinga
[(11)C]Preladenant was developed as a novel PET ligand for the adenosine A2A receptors (A2ARs). The present study aims to evaluate the suitability of [(11)C]preladenant-PET for the quantification of striatal A2ARs and the assessment of A2AR occupancy in the conscious monkey brain. METHODS: [(11)C]Preladenant was i.v. injected into conscious monkeys (n = 4, 18 PET scans) and a 91-min dynamic scan was started. Arterial blood samples in combination with metabolite analysis were obtained during the scan to provide the input function for kinetic modelling...
January 6, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
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