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https://www.readbyqxmd.com/read/28220900/membrane-cholesterol-access-into-a-g-protein-coupled-receptor
#1
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
#2
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...
February 13, 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
#3
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
#4
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
#5
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)...
February 6, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28153452/adenosine-receptors-modulators-of-lipid-availability-that-are-controlled-by-lipid-levels
#6
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
#7
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...
January 24, 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
#8
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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/28060732/prognostic-impact-of-cd73-and-a2a-adenosine-receptor-expression-in-non-small-cell-lung-cancer
#13
Yusuke Inoue, Katsuhiro Yoshimura, Nobuya Kurabe, Tomoaki Kahyo, Akikazu Kawase, Masayuki Tanahashi, Hiroshi Ogawa, Naoki Inui, Kazuhito Funai, Kazuya Shinmura, Hiroshi Niwa, Takafumi Suda, Haruhiko Sugimura
In immune cells, CD73 dephosphorylates and converts extracellular AMP into adenosine, which binds the A2A adenosine receptor (A2AR). Blockade of this interaction, which induces an immunosuppressed niche in the tumor microenvironment, represents a potential novel treatment strategy. The clinical significance of CD73 and A2AR expression in non-small-cell lung cancer (NSCLC), however, has yet to be thoroughly investigated. Here we evaluated CD73 and A2AR protein expression levels using immunohistochemistry in tissue microarrays containing 642 resected NSCLC specimens...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28042771/oxidative-stress-pro-inflammatory-cytokines-and-antioxidants-regulate-expression-levels-of-micrornas-in-parkinson-s-disease
#14
Kedar N Prasad
Parkinson's disease (PD) is a slow progressive neurodegenerative disease associated with abnormal function of extrapyramidal system. Although several biochemical and genetic defects have been identified, increased oxidative stress and chronic inflammation are one of the earliest events that initiate and promote PD. Oxidative stress also participates in impaired non-motor symptoms.The levels of microRNAs that are evolutionarily conserved single-stranded non-coding RNAs of approximately 22 nucleotide in length are altered in PD...
January 2, 2017: Current Aging Science
https://www.readbyqxmd.com/read/28041708/expressions-of-adenosine-a2a-receptors-in-coronary-arteries-and-peripheral-blood-mononuclear-cells-are-correlated-in-coronary-artery-disease-patients
#15
Vlad Gariboldi, Donato Vairo, Régis Guieu, Marion Marlingue, Eléonore Ravis, David Lagier, Alissa Mari, Elsa Thery, Frédéric Collart, Marine Gaudry, Laurent Bonello, Franck Paganelli, Jocelyne Condo, Nathalie Kipson, Emmanuel Fenouillet, Jean Ruf, Giovanna Mottola
BACKGROUND: Altered coronary blood flow occurs in patients with coronary artery disease (CAD). Adenosine strongly impacts blood flow mostly via adenosine A2A receptor (A2AR) expressed in coronary tissues. As part of a systemic regulation of the adenosinergic system, we compared A2AR expression in situ, and on peripheral blood mononuclear cells (PBMC) in CAD patients. METHODS AND RESULTS: Aortic and coronary tissues, and PBMC were sampled in 20 CAD patients undergoing coronary artery bypass surgery and consecutively included...
March 1, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28012867/chronic-oral-administration-of-mpep-an-antagonist-of-mglu5-receptor-during-gestation-and-lactation-alters-mglu5-and-a2a-receptors-in-maternal-and-neonatal-brain
#16
Antonio López-Zapata, David Agustín León-Navarro, María Crespo, José Luis Albasanz, Mairena Martín
Antidepressant and anxiolytic drugs are widely consumed even by pregnant and lactating women. The metabotropic glutamate receptor 5 (mGlu5) antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) exerts antidepressant- and anxiolytic-like actions. Given that treatment for anxiety and depression use to be prolonged in time, it is conceivable a possible modulation of metabotropic glutamate receptors (mGlu receptors) after prolonged MPEP exposure, which could also modify adenosine A2A receptors (A2AR) since functional cross-talk between them has been reported...
March 6, 2017: Neuroscience
https://www.readbyqxmd.com/read/28011152/adenosine-a2a-receptor-stimulation-blocks-development-of-nonalcoholic-steatohepatitis-in-mice-by-multilevel-inhibition-of-signals-that-cause-immunolipotoxicity
#17
Elisa Alchera, Simona Rolla, Chiara Imarisio, Valentina Bardina, Guido Valente, Francesco Novelli, Rita Carini
Lipotoxicity and immunoinflammation are associated with the evolution of steatosis toward nonalcoholic steatohepatitis (NASH). This study reports the ability of adenosine A2a receptor (A2aR) activation to inhibit NASH development by modulating the responses of CD4(+) T-helper (Th) cells to avoid an immuno-mediated potentiation of lipotoxicity. The effect of the A2aR agonist CGS21680 on immunoinflammatory signals, CD4(+)Th cell infiltration and immunolipotoxicity was analyzed in steatotic C57BL/6 mice fed with a methionine-choline-deficient (MCD) diet and in mouse hepatocytes exposed to palmitic acid (PA)...
December 6, 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/27986907/cutting-edge-adenosine-a2a-receptor-signals-inhibit-germinal-center-t-follicular-helper-cell-differentiation-during-the-primary-response-to-vaccination
#18
Shirdi E Schmiel, Jessica A Yang, Marc K Jenkins, Daniel L Mueller
Adenosine A2a receptor (A2aR) signaling acts as a barrier to autoimmunity by promoting anergy, inducing regulatory T cells, and inhibiting effector T cells. However, in vivo effects of A2aR signaling on polyclonal CD4 T cells during a primary response to foreign Ag has yet to be determined. To address this problem, we immunized mice with peptide Ag 2W1S coupled to PE in CFA and treated with the selective A2aR agonist CGS-21680 (CGS). 2W1S:I-A(b)-specific tetramer-binding CD4 T cells did not become anergic or differentiate into Foxp3(+) regulatory T cells...
January 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27984074/alterations-in-ventral-and-dorsal-striatal-allosteric-a2ar-d2r-receptor-receptor-interactions-after-amphetamine-challenge-relevance-for-schizophrenia
#19
Julia Pintsuk, Dasiel O Borroto-Escuela, Terence K Y Lai, Fang Liu, Kjell Fuxe
Striatal dopamine D2R homodimerization is increased in the dorsal striatum after acute amphetamine challenge and in the amphetamine-induced sensitized state, a well-known animal model of schizophrenia. Therefore, it was tested if the increase in D2R homoreceptor complexes found after acute amphetamine challenge in the saline or the amphetamine sensitized state leads to changes in the antagonistic adenosine A2AR-D2R interactions in the striatum. [(3)H]-raclopride binding was performed in membrane preparations from the ventral and dorsal striatum involving competition with the D2R like agonist quinpirole...
October 29, 2016: Life Sciences
https://www.readbyqxmd.com/read/27975140/profound-hypothermia-after-adenosine-kinase-inhibition-in-a1ar-deficient-mice-suggests-a-receptor-independent-effect-of-intracellular-adenosine
#20
Christoph Eisner, SooMi Kim, Alexandra Grill, Yan Qin, Marion Hoerl, Josephine Briggs, Hayo Castrop, Manfred Thiel, Jurgen Schnermann
Administration of the nucleoside adenosine has been shown to induce hypothermia in a number of species, an effect mediated predominantly by the adenosine 1 receptor (A1AR) subtype. The present experiments were performed to explore the possibility that the rise of intracellular adenosine levels expected to accompany adenosine administration may contribute to the hypothermic effect of adenosine independent of A1AR activation. Since phosphorylation of adenosine by adenosine kinase (ADK) is causal in the maintenance of low intracellular adenosine, we have examined the effect of ADK inhibition on core body temperature (CBT)...
December 14, 2016: Pflügers Archiv: European Journal of Physiology
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