DOCSLIB.ORG

5-HT2B Receptors Are Required for Serotonin-Selective Antidepressant

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
5-HT2B Receptors Are Required for Serotonin-Selective Antidepressant Molecular Psychiatry (2012) 17, 154–163 & 2012 Macmillan Publishers Limited All rights reserved 1359-4184/12 www.nature.com/mp IMMEDIATE COMMUNICATION 5-HT2B receptors are required for serotonin-selective antidepressant actions SL Diaz1,2,3, S Doly1,2,3, N Narboux-Neˆme1,2,3, S Ferna´ndez1,2,3, P Mazot1,2,3, SM Banas1,2,3, K Boutourlinsky1,2,3, I Moutkine1,2,3, A Belmer1,2,3, A Roumier1,2,3 and L Maroteaux1,2,3 1UMR-S839 INSERM, Paris, France; 2Universite´ Pierre et Marie Curie, Paris, France and 3Institut du Fer a` Moulin, Paris, France The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepres- sants are initially triggered by blocking the serotonin transporter and rely on long-term adaptations of pre- and post-synaptic receptors. We show here that long-term behavioral and neurogenic SSRI effects are abolished after either genetic or pharmacological inactivation of 5-HT2B receptors. Conversely, direct agonist stimulation of 5-HT2B receptors induces an SSRI-like response in behavioral and neurogenic assays. Moreover, the observation that (i) this receptor is expressed by raphe serotonergic neurons, (ii) the SSRI-induced increase in hippocampal extracellular serotonin concentration is strongly reduced in the absence of functional 5-HT2B receptors and (iii) a selective 5-HT2B agonist mimics SSRI responses, supports a positive regulation of serotonergic neurons by 5-HT2B receptors. The 5-HT2B receptor appears, therefore, to positively modulate serotonergic activity and to be required for the therapeutic actions of SSRIs. Consequently, the 5-HT2B receptor should be considered as a new tractable target in the combat against depression. Molecular Psychiatry (2012) 17, 154–163; doi:10.1038/mp.2011.159; published online 13 December 2011 Keywords: serotonin levels; 5-HT2B receptors; antidepressants; neurogenesis 11 Introduction lacking 5-HT2B receptors. Conversely, a 5-HT2B receptor agonist induced an antidepressant-like The most widely used antidepressants, the serotonin- action in the FST, suggesting that this receptor is selective reuptake inhibitors (SSRIs), induce an required for acute SSRI effects and might modulate increase in extracellular serotonin (5-hydroxytrypta- serotonergic tone. mine, 5-HT) concentrations by acutely blocking the 1,2 Blockage of SERT and increase of 5-HT levels are specific serotonin transporter (SERT). The SERT immediately attained after SSRI administration, regulates the extracellular serotonin concentration by 3 whereas therapeutic effects are only observed after removing 5-HT from the synaptic cleft, and diverse weeks of treatment. The delay before the onset of molecules modulate this activity, including the A3 clinical effects in depressive individuals appears to adenosine receptor4 and kinases such as PKG/p38 5 rely on the time required for stabilization of mono- mitogen-activated protein kinase. Previous studies amine levels and other neuroadaptations, including have suggested a functional interaction between neurogenesis.12 As well, regulation of 5-HT receptors SERT and the 5-HT2B receptor—a receptor implicated appears to be required for either the acute or chronic in 5-HT-dependent phenotypes, including impulsiv- 6 effects of SSRIs, as it was largely demonstrated ity, aggressivity and suicidality. Ex vivo studies have 12–16 for 5-HT1A, 5-HT2A, 5-HT2C and 5-HT4 receptors. indicated that 5-HT2B receptors might participate in 7 Importantly, < 50% of all patients with depression the control of SERT in raphe neurons, while in vivo show remission with optimized available antidepres- studies further confirmed that 5-HT2B receptors sant treatments.1 Despite extensive research, the contribute to the behavioral and physiological effects neurobiological mechanisms underlying antidepres- of the SERT-targeting 5-HT releasers, MDMA (the 8–10 sant effects or the resistance to antidepressants are club-drug ecstasy) and dexfenfluramine. Further- not yet well understood.17,18 Therefore, we studied more, we recently reported that the acute response to the chronic actions of SSRIs in behavioral and SSRIs in the forced swimming test (FST), a classical neurogenic assays, and SSRI-induced alterations in test for antidepressant activity, is absent in mice synaptic 5-HT levels in mice with genetic or pharma- cological ablation of 5-HT2B receptors, and demon- Correspondence: Dr L Maroteaux, Institut du Fer a` Moulin, UMR- strate herein that 5-HT2B receptors are required for S839 INSERM/UPMC, 17 rue du Fer a` Moulin, 75005 Paris. SSRI antidepressant acute and long-term effects, E-mail: [email protected] Received 8 June 2011; revised 5 October 2011; accepted 24 possibly by presynaptic modulation of extracellular October 2011; published online 13 December 2011 5-HT levels. 5-HT2B receptors in antidepressant responses SL Diaz et al 155 Materials and methods laboratory.8–10 All measurements were obtained from freely moving mice following injections of RS127445 Animals (0.5 mg kgÀ1, i.p.) and/or paroxetine (2 mg kgÀ1, i.p.) The 5-HTÀ/À mice used in all experiments are in a 2B (see supplementary Information). 129S2/SvPas (129S2) background,19 while SERTÀ/À and Pet-1À/À mice are on C57Bl/6NCrl background.20,21 À/À À/À Single-cell RT-PCR Adult (7–9-week-old) male 5-HT2B , SERT and Pet-1À/À mice, and their respective wild-type (WT) Pet-1-EGFP mice, generated from a cross of Pet-1- 23 24 control mice (originally obtained from Charles River CRE with RCE:loxP mice, were used for single-cell Laboratories, L’Arbresle, France), were derived from reverse-transcription (RT)-PCR experiments. Mice heterozygous crosses and were bred at our animal were anesthetized and decapitated, and the brain facility. All mice were maintained according to the was rapidly dissected out. Coronal slices (250 m European Directive directive 86/609/CEE. FST was thick) were prepared using a vibratome in artificial conducted as already described.22 The novelty-sup- cerebral spinal fluid supplemented with sucrose. The pressed feeding (NSF) test was basically conducted methodology involving harvesting of cytoplasmic as already described,17 with some modifications (see content and subsequent single-cell PCR amplification 25 Supplementary Information). has been described elsewhere. Chronic treatments, proliferation and survival assays, 5-HT1A receptor quantitative PCR and tissue preparation Raphe nucleus and hippocampus were dissected For all the drugs employed in this study, the lowest and homogenized in 1 ml of RNAsolv. Genomic DNA acute effective dose was selected based on our previous was removed by digestion with Amplification Grade data from WT mice.11 Fluoxetine (3 mg kgÀ1 per day in DNase I (Sigma-Aldrich, St Quentin Falavier, France). 129S2 or 10 mg kgÀ1 per day intraperitoneal (i.p.) in First-strand cDNA was synthesized by reverse trans- C57Bl6/6NCrl mice) or vehicle (0.9% NaCl) was cription of 3 mg of total RNA with Superscript-II injected once daily for 4 weeks. WT mice chronically reverse transcriptase (Invitrogen, Illkirch, France) treated with RS127445 continuously received the according to standard protocols. Reverse transcriptase À1 5-HT2B antagonist at 1 mg kg per day or vehicle (50% was omitted in some samples as negative control. dimethyl sulfoxide) via subcutaneous osmotic pumps Relative expression levels of 5-HT1A mRNA were (Alzets model 2004, L’Arbresle, France) for 4 weeks determined by real time RT-PCR using Absolute SYBR in addition to the daily i.p. injections of Flx or Veh. Green Mix (ABgene, Illkirch, France) and a set of The last day of this 4-week experimental protocol, primers specific for 5-HT1A receptor. 5-HT1A expres- mice received two injections of 150 mg kgÀ1 5-bromo- sion was normalized to mouse CyclophilinB mRNA 0 2 deoxyuridine (BrdU) (2-h interval between injections). expression. Data were analyzed with the 2–DCt Then, 24 h after BrdU administration, a pool of mice method, and values are expressed as the mean of four was perfused and the brains were recovered for cell separate experiments performed in duplicate. proliferation studies. Another pool of mice continued receiving the SSRI or vehicle for 4 more weeks after In situ hybridization BrdU administration, and was finally perfused and the Coronal sections from the same experimental subjects brains were recovered for cell survival studies. Similar used in immunohistochemistry studies were em- experimental protocols were conducted for cell prolif- ployed for in situ hybridization, which was perfor- eration induced by paroxetine (2 mg kgÀ1) or BW723C86 med as previously described26 on a pool of two (3 mg kgÀ1 per day in 129S2 or 10 mg kgÀ1 per day i.p. in coronal free-floating sections per mouse from each C57Bl6/6NCrl mice). All these drugs were injected once experimental group (WT-Veh; WT-Flx; 5-HTÀ/À-Veh daily, and at the end of the chronic treatments (24 h and 2B and 5-HTÀ/À-Flx). 5-HT (IMAGE:8861702) dig-UTP- 4 weeks after BrdU, respectively, for proliferation and 2B 1A labeled probe was used and detected using an anti- survival assays), mice were anesthetized and their body coupled to alkaline phosphatase (1/2000, Roche, brains were removed, fixed and processed for immu- Meylan, France). Alkaline phosphatase activity was nohistochemistry. See Supplementary Information. revealed using 4-nitroblue tetrazolium chloride/ Immunohistochemistry and immunofluorescence 5-bromo 4-chloro 3-indolyl phosphate. Newborn cells were detected by classical peroxidase immunostaining of BrdU, an exogenous marker of cell 8-OH-DPAT-induced hypothermia
Load more

Recommended publications
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • Bioinformatics Unmasks the Maneuverers of Pain Pathways In
    www.nature.com/scientificreports OPEN Bioinformatics Unmasks the Maneuverers of Pain Pathways in Acute Kidney Injury Received: 4 March 2019 Aprajita Gupta 1, Sanjeev Puri 2 & Veena Puri 1 Accepted: 31 July 2019 Acute Kidney injury (AKI) is one of the leading health concerns resulting in accumulation of nitrogenous Published: xx xx xxxx as well as non-nitrogenous wastes in body and characterised by a rapid deterioration in kidney functions. Besides the major toll from the primary insult in the kidney, consequential extra-renal secondary insults endowed with the pathways of infammatory milieu often complicates the disease outcome. Some of the known symptoms of AKI leading to clinical reporting are fatigue, loss of appetite, headache, nausea, vomiting, and pain in the fanks, wherein proinfammatory cytokines have been strongly implicated in pathogenesis of AKI and neuro-infammation. Taking in account these clues, we have tried to decode the neuro-infammation and pain perception phenomenon during the progression of AKI using the pathway integration and biological network strategies. The pathways and networks were generated using bioinformatics software viz. PANTHER, Genomatix and PathVisio to establish the relationship between immune and neuro related pathway in AKI. These observations envisage a neurol-renal axis that is predicted to involve calcium channels in neuro-infammatory pathway of AKI. These observations, thus, pave a way for a new paradigm in understanding the interplay of neuro- immunological signalling in AKI. Acute kidney injury (AKI) is a clinical event associated with a rapid loss of kidney function, leading to high mor- bidity and mortality1. Every year about 2 million people die from AKI due to late detection of disease or paucity of efective therapeutic interventions2.
    [Show full text]
  • Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells Amy Sue Bogard University of Tennessee Health Science Center
    University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 12-2013 Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells Amy Sue Bogard University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Medical Cell Biology Commons, and the Medical Molecular Biology Commons Recommended Citation Bogard, Amy Sue , "Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells" (2013). Theses and Dissertations (ETD). Paper 330. http://dx.doi.org/10.21007/etd.cghs.2013.0029. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Biomedical Sciences Track Molecular Therapeutics and Cell Signaling Research Advisor Rennolds Ostrom, Ph.D. Committee Elizabeth Fitzpatrick, Ph.D. Edwards Park, Ph.D. Steven Tavalin, Ph.D. Christopher Waters, Ph.D. DOI 10.21007/etd.cghs.2013.0029 Comments Six month embargo expired June 2014 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/330 Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Amy Sue Bogard December 2013 Copyright © 2013 by Amy Sue Bogard.
    [Show full text]
  • Adenosine-Mediated Effects of Ticagrelor Evidence and Potential Clinical Relevance
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 63, No. 23, 2014 Ó 2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2014.03.031 Adenosine-Mediated Effects of Ticagrelor Evidence and Potential Clinical Relevance Marco Cattaneo, MD,* Rainer Schulz, MD, PHD,y Sven Nylander, PHDz Milan, Italy; Giessen, Germany; and Mölndal, Sweden This review constitutes a critical evaluation of recent publications that have described an additional mode of action of the P2Y12 receptor antagonist ticagrelor. The effect is mediated by inhibition of the adenosine transporter ENT1 (type 1 equilibrative nucleoside transporter), which provides protection for adenosine from intracellular metabolism, thus increasing its concentration and biological activity, particularly at sites of ischemia and tissue injury where it is formed. Understanding the mode of action of ticagrelor is of particular interest given that its clinical profile, both in terms of efficacy and adverse events, differs from that of thienopyridine P2Y12 antagonists. (J Am Coll Cardiol 2014;63:2503–9) ª 2014 by the American College of Cardiology Foundation Ticagrelor is a direct-acting, reversibly binding P2Y12 Outcomes) study, ticagrelor was superior to clopidogrel in antagonist that provides rapid onset of antiplatelet effects preventing cardiovascular death, myocardial infarction, or after oral administration. P2Y12, 1 of the 2 purinergic stroke (9.8% vs. 11.7%, a 16% reduction) in patients with receptors for adenosine diphosphate (ADP) expressed by acute coronary syndrome (ACS); two-thirds of these pa- platelets, is essential for normal ADP-induced platelet tients had undergone percutaneous coronary intervention fi aggregation.
    [Show full text]
  • Adenosine Receptor Agonists Deepen the Inhibition of Platelet Aggregation
    Vascular Pharmacology 113 (2019) 47–56 Contents lists available at ScienceDirect Vascular Pharmacology journal homepage: www.elsevier.com/locate/vph Adenosine receptor agonists deepen the inhibition of platelet aggregation by T P2Y12 antagonists ⁎ Magdalena Boncler ,1, Joanna Wzorek1, Nina Wolska, Dawid Polak, Cezary Watala, Marcin Rozalski Department of Haemostasis and Haemostatic Disorders, Medical University of Lodz, Lodz, Poland ARTICLE INFO ABSTRACT Keywords: Several adenosine receptor (AR) agonists have been shown in the past to possess anti-platelet potential; however, Platelet the adjunctive role of AR agonists in anti-platelet therapy with the use of P2Y12 receptor inhibitors has not been Adenosine receptor elucidated so far. P2Y12 antagonist This in vitro aggregation-based study investigates whether the inhibition of platelet function mediated by Dual anti-platelet therapy cangrelor or prasugrel metabolite can be potentiated by AR agonists. It evaluates the effect of non-selective (2- Aggregation chloroadenosine), A2A-selective (UK 432097, MRE 0094, PSB 0777) and A2B-selective AR agonists (BAY 60- 6583) on platelet function in relation to their toxicity, specificity towards adenosine receptor subtypes, structure and solubility. UK 432097, 2-chloroadenosine, MRE 0094 and PSB 0777 were found to be more or less potent inhibitors of ADP-induced platelet aggregation when acting alone, and that they remained non-cytotoxic to the cells. These AR agonists were also effective in the potentiation of the effects exerted12 byP2Y antagonists. Considering the estimated IC50 value, UK 432097, showing a relatively high binding affinity to the2A A adenosine receptor, has been identified as the most potent anti-aggregatory agent. This compound diminished platelet aggregation at nanomolar concentrations and further augmented platelet inhibition by P2Y12 antagonists by approx.
    [Show full text]
  • Adenosine Receptor Binding: Structureactivity Analysis Generates Extremely Potent Xanthine Antagonists (N6-Cyclohexyladenosine/Theophylline) ROBERT F
    Proc. Natl Acad. Sci. USA Vol. 80, pp. 2077-2080, April 1983 Neurobiology Adenosine receptor binding: Structureactivity analysis generates extremely potent xanthine antagonists (N6-cyclohexyladenosine/theophylline) ROBERT F. BRUNS*tt, JOHN W. DALY*, AND SOLOMON H. SNYDERt§ *National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20205; and tDepartments of Neuroscience, of Pharmacology and Experimental Therapeutics, and of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205 Contributed by Solomon H. Snyder, December 30, 1982 ABSTRACT Structure-activity analysis of alkylxanthine de- bind to the Al subtype of adenosine receptor (14), which is rivatives at adenosine receptor binding sites has been employed localized to synaptic zones in the brain associated in part with to design more potent adenosine receptor antagonists. Receptor excitatory axonal projections (16, 17). Al receptors inhibit affinities of xanthines were determined by measuring inhibition adenylate cyclase, as reflected by their GTP regulation (18, of the binding of N6-[3H]cyclohexyladenosine to bovine brain 19), have a nanomolar affinity for adenosine, and have a higher membranes. 1,3-Dipropyl substitutions enhance potency com- affinity for N6(L-phenylisopropyl)adenosine (L-PIA) than for pared to the 1,3-dimethyl substitution in theophylline. An 8-phenyl 5'-N-ethylcarboxamide adenosine, whereas A2 receptors stim- substituent produces a considerable increase in potency, which ulate adenylate cyclase, have micromolar affinity for adeno- is augmented by certain para substitutions on the 8-phenyl ring. and have a Combining an ortho amino with a para-chloro substituent on the sine, higher affinity for 5'-N-ethylcarboxamide 8-phenyl ring affords further increases in potency.
    [Show full text]
  • Crystal Structure of the Adenosine A2A Receptor Bound to an Antagonist Reveals a Potential Allosteric Pocket
    Crystal structure of the adenosine A2A receptor bound to an antagonist reveals a potential allosteric pocket Bingfa Suna, Priti Bachhawata, Matthew Ling-Hon Chua, Martyn Woodb, Tom Ceskac, Zara A. Sandsd, Joel Mercierd, Florence Lebond, Tong Sun Kobilkaa, and Brian K. Kobilkaa,e,1 aConfometRx, Inc., Santa Clara, CA 95054; bDiscovery Biology, New Medicines, UCB Pharma, B-1420 Braine-l’Alleud, Belgium; cDepartment of Structural Biology, New Medicines, UCB Pharma, Slough SL1 3WE, United Kingdom; dDiscovery Chemistry, New Medicines, UCB Pharma, B-1420 Braine-l’Alleud, Belgium and eDepartment of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305 Contributed by Brian K. Kobilka, December 29, 2016 (sent for review October 17, 2016; reviewed by Oliver P. Ernst and Nagarajan Vaidehi) The adenosine A2A receptor (A2AR) has long been implicated in for longer than when administered separately at the same dose in a cardiovascular disorders. As more selective A2AR ligands are being rodent model of PD (6). In an effort to identify a dual compound ’ identified, its roles in other disorders, such as Parkinson s disease, displaying A2AR as well as NR2B receptor antagonist activities, are starting to emerge, and A2AR antagonists are important drug Cmpd-1 was designed and synthesized. The compound binds to both candidates for nondopaminergic anti-Parkinson treatment. Here receptors with high affinity (Table 1). To understand the structure– we report the crystal structure of A2A receptor bound to com- activity relationship around the chemical series for the A2ARand N pound 1 (Cmpd-1), a novel A2AR/ -methyl D-aspartate receptor facilitate further optimization, we sought to obtain the crystal subtype 2B (NR2B) dual antagonist and potential anti-Parkinson structure of the A2AR in complex with Cmpd-1.
    [Show full text]