Crystal Structure of the Adenosine A2A Receptor Bound to an Antagonist Reveals a Potential Allosteric Pocket
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P2Y6 Receptors Regulate CXCL10 Expression and Secretion in Mouse Intestinal Epithelial Cells
fphar-09-00149 February 26, 2018 Time: 17:57 # 1 ORIGINAL RESEARCH published: 28 February 2018 doi: 10.3389/fphar.2018.00149 P2Y6 Receptors Regulate CXCL10 Expression and Secretion in Mouse Intestinal Epithelial Cells Mabrouka Salem1,2, Alain Tremblay2, Julie Pelletier2, Bernard Robaye3 and Jean Sévigny1,2* 1 Département de Microbiologie-Infectiologie et d’Immunologie, Faculté de Médecine, Université Laval, Québec City, QC, Canada, 2 Centre de Recherche du CHU de Québec – Université Laval, Québec City, QC, Canada, 3 Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Gosselies, Belgium In this study, we investigated the role of extracellular nucleotides in chemokine (KC, MIP- 2, MCP-1, and CXCL10) expression and secretion by murine primary intestinal epithelial cells (IECs) with a focus on P2Y6 receptors. qRT-PCR experiments showed that P2Y6 was the dominant nucleotide receptor expressed in mouse IEC. In addition, the P2Y6 Edited by: ligand UDP induced expression and secretion of CXCL10. For the other studies, we Kenneth A. Jacobson, −=− National Institutes of Health (NIH), took advantage of mice deficient in P2Y6 (P2ry6 ). Similar expression levels of P2Y1, −=− United States P2Y2, P2X2, P2X4, and A2A were detected in P2ry6 and WT IEC. Agonists of Reviewed by: TLR3 (poly(I:C)), TLR4 (LPS), P2Y1, and P2Y2 increased the expression and secretion Fernando Ochoa-Cortes, of CXCL10 more prominently in P2ry6−=− IEC than in WT IEC. CXCL10 expression Universidad Autónoma de San Luis −=− Potosí, Mexico and secretion induced by poly(I:C) in both P2ry6 and WT IEC were inhibited by Markus Neurath, general P2 antagonists (suramin and Reactive-Blue-2), by apyrase, and by specific Universitätsklinikum Erlangen, Germany antagonists of P2Y1, P2Y2, P2Y6 (only in WT), and P2X4. -
Immunosuppression Via Adenosine Receptor Activation by Adenosine
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref RESEARCH ARTICLE elifesciences.org Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells Hiroshi Yamaguchi1, Toshihiko Maruyama2, Yoshihiro Urade2†, Shigekazu Nagata1,3* 1Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan; 3Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kyoto, Japan Abstract Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic *For correspondence: snagata@ supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an mfour.med.kyoto-u.ac.jp ecto-5’-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced † Present address: Molecular high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated Sleep Biology Laboratory, that AMP from apoptotic cells suppresses inflammation as a ‘calm down’ signal. WPI-International Institute for DOI: 10.7554/eLife.02172.001 Integrative Sleep Medicine, University of Tsukuba, Ibaraki, Japan Competing interests: The Introduction authors declare that no competing interests exist. -
Extracellular Adenosine Triphosphate and Adenosine in Cancer
Oncogene (2010) 29, 5346–5358 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW Extracellular adenosine triphosphate and adenosine in cancer J Stagg and MJ Smyth Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia Adenosine triphosphate (ATP) is actively released in the mulated the hypothesis of purinergic neurotransmission extracellular environment in response to tissue damage (Burnstock, 1972). Burnstock’s hypothesis that ATP and cellular stress. Through the activation of P2X and could be released by cells to perform intercellular P2Y receptors, extracellular ATP enhances tissue repair, signaling was initially met with skepticism, as it seemed promotes the recruitment of immune phagocytes and unlikely that a molecule that acts as an intracellular dendritic cells, and acts as a co-activator of NLR family, source of energy would also function as an extracellular pyrin domain-containing 3 (NLRP3) inflammasomes. messenger. Nevertheless, Burnstock pursued his work The conversion of extracellular ATP to adenosine, in and, together with Che Su and John Bevan, reported contrast, essentially through the enzymatic activity of the that ATP was also released from sympathetic nerves ecto-nucleotidases CD39 and CD73, acts as a negative- during stimulation (Su et al., 1971). Three decades later, feedback mechanism to prevent excessive immune responses. following the cloning and characterization of ATP and Here we review the effects of extracellular ATP and adenosine adenosine cell surface receptors, purinergic signaling is a on tumorigenesis. First, we summarize the functions of well-established concept and constitutes an expanding extracellular ATP and adenosine in the context of tumor field of research in health and disease, including cancer immunity. -
P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases
International Journal of Molecular Sciences Review P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases Derek Strassheim 1, Alexander Verin 2, Robert Batori 2 , Hala Nijmeh 3, Nana Burns 1, Anita Kovacs-Kasa 2, Nagavedi S. Umapathy 4, Janavi Kotamarthi 5, Yash S. Gokhale 5, Vijaya Karoor 1, Kurt R. Stenmark 1,3 and Evgenia Gerasimovskaya 1,3,* 1 The Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Aurora, CO 80045, USA; [email protected] (D.S.); [email protected] (N.B.); [email protected] (V.K.); [email protected] (K.R.S.) 2 Vascular Biology Center, Augusta University, Augusta, GA 30912, USA; [email protected] (A.V.); [email protected] (R.B.); [email protected] (A.K.-K.) 3 The Department of Pediatrics, Division of Critical Care Medicine, University of Colorado Denver, Aurora, CO 80045, USA; [email protected] 4 Center for Blood Disorders, Augusta University, Augusta, GA 30912, USA; [email protected] 5 The Department of BioMedical Engineering, University of Wisconsin, Madison, WI 53706, USA; [email protected] (J.K.); [email protected] (Y.S.G.) * Correspondence: [email protected]; Tel.: +1-303-724-5614 Received: 25 August 2020; Accepted: 15 September 2020; Published: 18 September 2020 Abstract: Purinergic G-protein-coupled receptors are ancient and the most abundant group of G-protein-coupled receptors (GPCRs). The wide distribution of purinergic receptors in the cardiovascular system, together with the expression of multiple receptor subtypes in endothelial cells (ECs) and other vascular cells demonstrates the physiological importance of the purinergic signaling system in the regulation of the cardiovascular system. -
Inosine Binds to A3 Adenosine Receptors and Stimulates Mast Cell Degranulation
Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation. X Jin, … , B R Duling, J Linden J Clin Invest. 1997;100(11):2849-2857. https://doi.org/10.1172/JCI119833. Research Article We investigated the mechanism by which inosine, a metabolite of adenosine that accumulates to > 1 mM levels in ischemic tissues, triggers mast cell degranulation. Inosine was found to do the following: (a) compete for [125I]N6- aminobenzyladenosine binding to recombinant rat A3 adenosine receptors (A3AR) with an IC50 of 25+/-6 microM; (b) not bind to A1 or A2A ARs; (c) bind to newly identified A3ARs in guinea pig lung (IC50 = 15+/-4 microM); (d) lower cyclic AMP in HEK-293 cells expressing rat A3ARs (ED50 = 12+/-5 microM); (e) stimulate RBL-2H3 rat mast-like cell degranulation (ED50 = 2.3+/-0.9 microM); and (f) cause mast cell-dependent constriction of hamster cheek pouch arterioles that is attenuated by A3AR blockade. Inosine differs from adenosine in not activating A2AARs that dilate vascular smooth muscle and inhibit mast cell degranulation. The A3 selectivity of inosine may explain why it elicits a monophasic arteriolar constrictor response distinct from the multiphasic dilator/constrictor response to adenosine. Nucleoside accumulation and an increase in the ratio of inosine to adenosine may provide a physiologic stimulus for mast cell degranulation in ischemic or inflamed tissues. Find the latest version: https://jci.me/119833/pdf Inosine Binds to A3 Adenosine Receptors and Stimulates Mast Cell Degranulation Xiaowei Jin,* Rebecca K. Shepherd,‡ Brian R. Duling,‡ and Joel Linden‡§ *Department of Biochemistry, ‡Department of Molecular Physiology and Biological Physics, and §Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908 Abstract Mast cells are found in the lung where they release media- tors that constrict bronchiolar smooth muscle. -
Adenosine Challenge Information for Patients Your Doctor Has Recommended That You Have an Adenosine Challenge
Adenosine challenge Information for patients Your doctor has recommended that you have an adenosine challenge. The purpose of this test is to see if you have an accessory pathway called ‘Wolff-Parkinson-White (WPW) syndrome’. What is an accessory pathway? This is an extra electrical connection between the top chambers (atria) and bottom chambers (ventricles) of the heart. This extra electrical connection may allow electrical signals to bypass the normal route in your heart and form a short circuit. This can result in your heart beating abnormally fast for periods of time, which is called supra-ventricular tachycardia (SVT). This is not usually dangerous, but can cause unpleasant symptoms, such as a racing heart (palpitations), dizziness, chest pain, shortness of breath or, rarely, may cause you to collapse. Although the extra connection is present from birth (congenital), symptoms may not develop until later in life. In some cases, WPW syndrome may be life-threatening, particularly if it occurs alongside a type of irregular heartbeat called atrial fibrillation. However, this is rare and treatment can completely remove this risk. page 2 How is an accessory pathway diagnosed? Adenosine is the drug used in this test. It belongs to a group of medicines called anti-arrhythmics. Adenosine blocks electrical signals through the atrio-ventricular (AV) node. This means signals cannot travel from the top to the bottom chambers of the heart for a few seconds, until the drug effects wear off. If an accessory pathway (extra connection) is present, the electrical signals can still travel down to the ventricles, and this will show up on the ECG. -
Lethality of Adenosine for Cultured Mammalian Cells by Interference with Pyrimidine Biosynthesis
J. Cell Set. 13, 429-439 (i973) 429 Printed in Great Britain LETHALITY OF ADENOSINE FOR CULTURED MAMMALIAN CELLS BY INTERFERENCE WITH PYRIMIDINE BIOSYNTHESIS K. ISHII* AND H. GREEN Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, U.S.A. SUMMARY Adenosine at low concentration is toxic to mammalian cells in culture. This may escape notice because some sera (such as calf or human) commonly used in culture media, contain adenosine deaminase. In the absence of serum deaminase, adenosine produced inhibition of growth of a number of established cell lines at concentrations as low as 5 x io~* M, and killed at 2 x io~5 M. This effect required the presence of cellular adenosine kinase, since a mutant line deficient in this enzyme was 70-fold less sensitive to adenosine. The toxic substance is therefore derived from adenosine by phosphorylation, and is probably one of the adenosine nucleotides. The toxic effect of adenosine in concentrations up to 2 x io~* M was completely prevented by the addition of uridine or of pyrimidines potentially convertible to uridine, suggesting that the adenosine was interfering with endogenous synthesis of uridylate. In the presence of adenosine, the conversion of labelled aspartate to uridine nucleotides was reduced by 80-85 %> and labelled orotate accumulated in both the cells and in the culture medium. The lethality of adenosine results from inhibition by one of its nucleotide products of the synthesis of uridylate at the stage of phosphoribosylation of orotate. INTRODUCTION Though adenosine is not an intermediate on the endogenous pathway of purine biosynthesis, it can be efficiently utilized through the purine salvage pathways as the sole purine source in cultured mammalian cells whose endogenous purine synthesis is blocked by aminopterin (Green & Ishii, 1972). -
Inosine in Biology and Disease
G C A T T A C G G C A T genes Review Inosine in Biology and Disease Sundaramoorthy Srinivasan 1, Adrian Gabriel Torres 1 and Lluís Ribas de Pouplana 1,2,* 1 Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, 08028 Barcelona, Catalonia, Spain; [email protected] (S.S.); [email protected] (A.G.T.) 2 Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Catalonia, Spain * Correspondence: [email protected]; Tel.: +34-934034868; Fax: +34-934034870 Abstract: The nucleoside inosine plays an important role in purine biosynthesis, gene translation, and modulation of the fate of RNAs. The editing of adenosine to inosine is a widespread post- transcriptional modification in transfer RNAs (tRNAs) and messenger RNAs (mRNAs). At the wobble position of tRNA anticodons, inosine profoundly modifies codon recognition, while in mRNA, inosines can modify the sequence of the translated polypeptide or modulate the stability, localization, and splicing of transcripts. Inosine is also found in non-coding and exogenous RNAs, where it plays key structural and functional roles. In addition, molecular inosine is an important secondary metabolite in purine metabolism that also acts as a molecular messenger in cell signaling pathways. Here, we review the functional roles of inosine in biology and their connections to human health. Keywords: inosine; deamination; adenosine deaminase acting on RNAs; RNA modification; translation Citation: Srinivasan, S.; Torres, A.G.; Ribas de Pouplana, L. Inosine in 1. Introduction Biology and Disease. Genes 2021, 12, 600. https://doi.org/10.3390/ Inosine was one of the first nucleobase modifications discovered in nucleic acids, genes12040600 having been identified in 1965 as a component of the first sequenced transfer RNA (tRNA), tRNAAla [1]. -
Blood Platelet Adenosine Receptors As Potential Targets for Anti-Platelet Therapy
International Journal of Molecular Sciences Review Blood Platelet Adenosine Receptors as Potential Targets for Anti-Platelet Therapy Nina Wolska and Marcin Rozalski * Department of Haemostasis and Haemostatic Disorders, Chair of Biomedical Science, Medical University of Lodz, 92-215 Lodz, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-504-836-536 Received: 30 September 2019; Accepted: 1 November 2019; Published: 3 November 2019 Abstract: Adenosine receptors are a subfamily of highly-conserved G-protein coupled receptors. They are found in the membranes of various human cells and play many physiological functions. Blood platelets express two (A2A and A2B) of the four known adenosine receptor subtypes (A1,A2A, A2B, and A3). Agonization of these receptors results in an enhanced intracellular cAMP and the inhibition of platelet activation and aggregation. Therefore, adenosine receptors A2A and A2B could be targets for anti-platelet therapy, especially under circumstances when classic therapy based on antagonizing the purinergic receptor P2Y12 is insufficient or problematic. Apart from adenosine, there is a group of synthetic, selective, longer-lasting agonists of A2A and A2B receptors reported in the literature. This group includes agonists with good selectivity for A2A or A2B receptors, as well as non-selective compounds that activate more than one type of adenosine receptor. Chemically, most A2A and A2B adenosine receptor agonists are adenosine analogues, with either adenine or ribose substituted by single or multiple foreign substituents. However, a group of non-adenosine derivative agonists has also been described. This review aims to systematically describe known agonists of A2A and A2B receptors and review the available literature data on their effects on platelet function. -
The Interaction of Selective A1 and A2A Adenosine Receptor Antagonists with Magnesium and Zinc Ions in Mice: Behavioural, Biochemical and Molecular Studies
International Journal of Molecular Sciences Article The Interaction of Selective A1 and A2A Adenosine Receptor Antagonists with Magnesium and Zinc Ions in Mice: Behavioural, Biochemical and Molecular Studies Aleksandra Szopa 1,* , Karolina Bogatko 1, Mariola Herbet 2 , Anna Serefko 1 , Marta Ostrowska 2 , Sylwia Wo´sko 1, Katarzyna Swi´ ˛ader 3, Bernadeta Szewczyk 4, Aleksandra Wla´z 5, Piotr Skałecki 6, Andrzej Wróbel 7 , Sławomir Mandziuk 8, Aleksandra Pochodyła 3, Anna Kudela 2, Jarosław Dudka 2, Maria Radziwo ´n-Zaleska 9, Piotr Wla´z 10 and Ewa Poleszak 1,* 1 Chair and Department of Applied and Social Pharmacy, Laboratory of Preclinical Testing, Medical University of Lublin, 1 Chod´zkiStreet, PL 20–093 Lublin, Poland; [email protected] (K.B.); [email protected] (A.S.); [email protected] (S.W.) 2 Chair and Department of Toxicology, Medical University of Lublin, 8 Chod´zkiStreet, PL 20–093 Lublin, Poland; [email protected] (M.H.); [email protected] (M.O.); [email protected] (A.K.) [email protected] (J.D.) 3 Chair and Department of Applied and Social Pharmacy, Medical University of Lublin, 1 Chod´zkiStreet, PL 20–093 Lublin, Poland; [email protected] (K.S.);´ [email protected] (A.P.) 4 Department of Neurobiology, Polish Academy of Sciences, Maj Institute of Pharmacology, 12 Sm˛etnaStreet, PL 31–343 Kraków, Poland; [email protected] 5 Department of Pathophysiology, Medical University of Lublin, 8 Jaczewskiego Street, PL 20–090 Lublin, Poland; [email protected] Citation: Szopa, A.; Bogatko, K.; 6 Department of Commodity Science and Processing of Raw Animal Materials, University of Life Sciences, Herbet, M.; Serefko, A.; Ostrowska, 13 Akademicka Street, PL 20–950 Lublin, Poland; [email protected] M.; Wo´sko,S.; Swi´ ˛ader, K.; Szewczyk, 7 Second Department of Gynecology, 8 Jaczewskiego Street, PL 20–090 Lublin, Poland; B.; Wla´z,A.; Skałecki, P.; et al. -
Adenosine A1 Receptor-Mediated Activation of Phospholipase C in Cultured Astrocytes Depends on the Level of Receptor Expression
The Journal of Neuroscience, July 1, 1997, 17(13):4956–4964 Adenosine A1 Receptor-Mediated Activation of Phospholipase C in Cultured Astrocytes Depends on the Level of Receptor Expression Knut Biber,1,2 Karl-Norbert Klotz,3 Mathias Berger,1 Peter J. Gebicke-Ha¨ rter,1 and Dietrich van Calker1 1Department of Psychiatry, University of Freiburg, D-79104 Freiburg, Germany, 2Institute for Biology II, University of Freiburg, D-79104 Freiburg, Germany, and 3Institute for Pharmacology and Toxicology, University of Wu¨ rzburg, D-97078 Wu¨ rzburg, Germany Adenosine A1 receptors induce an inhibition of adenylyl cyclase dependent on the expression level of A1 receptor, and (4) the via G-proteins of the Gi/o family. In addition, simultaneous potentiating effect on PLC activity is unrelated to extracellular stimulation of A1 receptors and of receptor-mediated activation glutamate. of phospholipase C (PLC) results in a synergistic potentiation of Taken together, our data support the notion that bg subunits PLC activity. Evidence has accumulated that Gbg subunits are the relevant signal transducers for A1 receptor-mediated mediate this potentiating effect. However, an A1 receptor- PLC activation in rat astrocytes. Because of the lower affinity of mediated increase in extracellular glutamate was suggested to bg, as compared with a subunits, more bg subunits are re- be responsible for the potentiating effect in mouse astrocyte quired for PLC activation. Therefore, only in cultures with higher cultures. We have investigated the synergistic activation of PLC levels of adenosine A1 receptors is the release of bg subunits by adenosine A1 and a1 adrenergic receptors in primary cul- via Gi/o activation sufficient to stimulate PLC. -
G Protein-Coupled Receptor Heteromers Are Key Players in Substance Use Disorder
G protein-coupled receptor heteromers are key players in substance use disorder. Lyes Derouiche, Dominique Massotte To cite this version: Lyes Derouiche, Dominique Massotte. G protein-coupled receptor heteromers are key players in substance use disorder.. Neuroscience & Biobehavioral Reviews, Oxford: Elsevier Ltd., 2019, 106, 10.1016/j.neubiorev.2018.09.026. hal-02264889 HAL Id: hal-02264889 https://hal.archives-ouvertes.fr/hal-02264889 Submitted on 18 Mar 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. G Protein-Coupled Receptor Heteromers Are Key Players in Substance Use Disorder. Lyes Derouiche and Dominique Massotte* Institut des Neurosciences Cellulaires et Integratives, UPR 3212 5 rue Blaise Pascal, F-67000 Strasbourg, France Highlights Heteromers are functional entities with behavioral impact Heteromers are increasingly recognized as key players in substance use disorder Heteromers may be part of larger functional multiprotein complexes Heteromers represent emerging innovative therapeutic targets Funding sources: The work was received the financial support of the Fondation pour la Recherche Médicale (DPA20140129364), the CNRS and the University of Strasbourg. L. Derouiche was the recipient of an IDEX post-doctoral fellowship of the University of Strasbourg. * Author for correspondence : Dominique Massotte, INCI UPR 3212, 5 rue Blaise Pascal, F-67000 Strasbourg, France, email: [email protected] 1 Abstract G protein–coupled receptors (GPCR) represent the largest family of membrane proteins in the human genome.