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Is TAAR1 a Potential Therapeutic Target for Immune Dysregulation In
Graduate Physical and Life Sciences PhD Pharmacology Abstract ID# 1081 Is TAAR1 a Potential Therapeutic Target for Immune Dysregulation in Drug Abuse? Fleischer, Lisa M; Tamashunas, Nina and Miller, Gregory M Addiction Sciences Laboratory, Northeastern University, Boston MA 02115 Abstract Discovered in 2001, Trace Amine Associated Receptor 1 (TAAR1) is a direct target of Data and Results amphetamine, methamphetamine and MDMA. It is expressed in the brain reward circuity and modulates dopamine transporter function and dopamine neuron firing rates. Newly-developed compounds that specifically target TAAR1 have recently been investigated in animal models In addition to brain, TAAR1 is expressed in immune cells METH promotes PKA and PKC Phosphorylation through TAAR1 as candidate therapeutics for methamphetamine, cocaine and alcohol abuse. These studies • We treated HEK/TAAR1 cells and HEK293 involving classic behavioral measures of drug response, as well as drug self-administration, Rhesus and Human cells with vehicle or METH, with and without strongly implicate TAAR1 as a potential therapeutic target for the treatment of addiction. In activators and inhibitors of PKA and PKC. addition to its central actions, we demonstrated that TAAR1 is upregulated in peripheral blood Cells Lines mononuclear cells (PBMC) and B cells following immune activation, and that subsequent • We performed Western blotting experiments to activation of TAAR1 by methamphetamine stimulates cAMP, similar to the function of measure levels of phospho-PKA and phospho- adenosine A2 receptors which are also present in immune cells and play a critical role in the PKC. immune response. Here, we are investigating the relationship between TAAR1 and the • We found that specific activators of PKA and adenosine A2 receptor at the level of cellular signaling and receptor dimerization. -
4695389.Pdf (3.200Mb)
Non-classical amine recognition evolved in a large clade of olfactory receptors The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Li, Qian, Yaw Tachie-Baffour, Zhikai Liu, Maude W Baldwin, Andrew C Kruse, and Stephen D Liberles. 2015. “Non-classical amine recognition evolved in a large clade of olfactory receptors.” eLife 4 (1): e10441. doi:10.7554/eLife.10441. http://dx.doi.org/10.7554/ eLife.10441. Published Version doi:10.7554/eLife.10441 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:23993622 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA RESEARCH ARTICLE Non-classical amine recognition evolved in a large clade of olfactory receptors Qian Li1, Yaw Tachie-Baffour1, Zhikai Liu1, Maude W Baldwin2, Andrew C Kruse3, Stephen D Liberles1* 1Department of Cell Biology, Harvard Medical School, Boston, United States; 2Department of Organismic and Evolutionary Biology, Museum of Comparative Zoology, Harvard University, Cambridge, United States; 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States Abstract Biogenic amines are important signaling molecules, and the structural basis for their recognition by G Protein-Coupled Receptors (GPCRs) is well understood. Amines are also potent odors, with some activating olfactory trace amine-associated receptors (TAARs). Here, we report that teleost TAARs evolved a new way to recognize amines in a non-classical orientation. -
Neurotransmitters-Drugs Andbrain Function.Pdf
Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Edited by R. A. Webster Department of Pharmacology, University College London, UK JOHN WILEY & SONS, LTD Chichester Á New York Á Weinheim Á Brisbane Á Singapore Á Toronto Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Copyright # 2001 by John Wiley & Sons Ltd. Bans Lane, Chichester, West Sussex PO19 1UD, UK National 01243 779777 International ++44) 1243 779777 e-mail +for orders and customer service enquiries): [email protected] Visit our Home Page on: http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1P0LP,UK, without the permission in writing of the publisher. Other Wiley Editorial Oces John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, USA WILEY-VCH Verlag GmbH, Pappelallee 3, D-69469 Weinheim, Germany John Wiley & Sons Australia, Ltd. -
Jenna K. Caines, Sherri L. Christian, Mark D. Berry Department of Biochemistry, Memorial University of Newfoundland, St. John'
Trace Amine-Associated Receptors in Monocytes: A Constant Low-Level Expression Jenna K. Caines, Sherri L. Christian, Mark D. Berry Department of Biochemistry, Memorial University of Newfoundland, St. John’s NL Trace amine-associated receptors (TAARs) Is TAAR1 differentially expressed in response to Pro- and Are any TAARs differentially expressed between § G protein-coupled receptors anti-inflammatory stimuli? monocyte and macrophage lineages? § Established throughout the body in vertebrates Table 1: Datasets with n ≥ 3 examining human and mice macrophages Table 2: Datasets with n ≥ 3 containing several monocyte and § Humans have 6 functional isoforms: TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9 treated with pro- and anti-inflammatory stimuli macrophage lineages from mice TAARs and the immune system Dataset Treatment Time TAAR1 p-value Dataset Cell type Number of lineages Treatment § Found in leukocyte populations1 GSE53986 Untreated (control) 0h examined INFγ 24h 0.8 GSE15907 Lung Macrophage 2 NA 1 § TAAR1 suspected of regulating immune response GSE60290 Untreated (control) 0h Peritoneal Macrophage 6 NA § Potential target for pharmacological treatment of immune disorders2 INFγ 18h 0.3 Spleen Macrophage NA GSE43075 Untreated (control) 0h Blood Monocyte 2 NA Hypothesis LPS 4h 0.45 Mesenteric LN monocyte 1 NA GSE121646 Untreated (control) 0h Oral Salmonella § TAAR1 will show differential expression upon activation and LPS 8h 0.7 Small intestine macrophage 2 Typhimurium(72 h) GSE19315 Untreated (control) 0h between leukocyte populations -
Effects of the Trace Amine Associated Receptor 1 Agonist RO5263397 On
International Journal of Neuropsychopharmacology, 2015, 1–7 doi:10.1093/ijnp/pyu060 Research Article research article Effects of the Trace Amine Associated Receptor 1 Agonist RO5263397 on Abuse-Related Behavioral Indices of Methamphetamine in Rats Li Jing, PhD; Yanan Zhang, PhD; Jun-Xu Li, PhD Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY (Drs Jing and Li); Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China (Dr Jing); Research Triangle Institute, Research Triangle Park, NC (Dr Zhang). Correspondence: Jun-Xu Li, PhD, Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY ([email protected]). Abstract Background: Methamphetamine is a major drug of abuse with no effective pharmacotherapy available. Trace amine associated receptor 1 is implicated in cocaine addiction and represents a potential therapeutic target. However, the effects of trace amine associated receptor 1 agonists on addiction-related behavioral effects of methamphetamine are unknown. Methods: This study examined the effects of a trace amine associated receptor 1 agonist RO5263397 on methamphetamine- induced behavioral sensitization, methamphetamine self-administration, cue- and methamphetamine-induced reinstatement of drug seeking, and cue-induced reinstatement of sucrose-seeking behaviors in rats. Male Sprague-Dawley rats were used to examine the effects of methamphetamine alone and in combination with the trace amine associated receptor 1 agonist RO5263397 (3.2–10 mg/kg). Results: RO5263397 dose-dependently attenuated the expression of behavioral sensitization to methamphetamine, reduced methamphetamine self-administration, and decreased both cue- and a priming dose of methamphetamine-induced reinstatement of drug-seeking behaviors. -
Tyramine and Amyloid Beta 42: a Toxic Synergy
biomedicines Article Tyramine and Amyloid Beta 42: A Toxic Synergy Sudip Dhakal and Ian Macreadie * School of Science, RMIT University, Bundoora, VIC 3083, Australia; [email protected] * Correspondence: [email protected]; Tel.: +61-3-9925-6627 Received: 5 May 2020; Accepted: 27 May 2020; Published: 30 May 2020 Abstract: Implicated in various diseases including Parkinson’s disease, Huntington’s disease, migraines, schizophrenia and increased blood pressure, tyramine plays a crucial role as a neurotransmitter in the synaptic cleft by reducing serotonergic and dopaminergic signaling through a trace amine-associated receptor (TAAR1). There appear to be no studies investigating a connection of tyramine to Alzheimer’s disease. This study aimed to examine whether tyramine could be involved in AD pathology by using Saccharomyces cerevisiae expressing Aβ42. S. cerevisiae cells producing native Aβ42 were treated with different concentrations of tyramine, and the production of reactive oxygen species (ROS) was evaluated using flow cytometric cell analysis. There was dose-dependent ROS generation in wild-type yeast cells with tyramine. In yeast producing Aβ42, ROS levels generated were significantly higher than in controls, suggesting a synergistic toxicity of Aβ42 and tyramine. The addition of exogenous reduced glutathione (GSH) was found to rescue the cells with increased ROS, indicating depletion of intracellular GSH due to tyramine and Aβ42. Additionally, tyramine inhibited the respiratory growth of yeast cells producing GFP-Aβ42, while there was no growth inhibition when cells were producing GFP. Tyramine was also demonstrated to cause increased mitochondrial DNA damage, resulting in the formation of petite mutants that lack respiratory function. -
Discovery of Novel Imidazolines and Imidazoles As Selective TAAR1
Discovery of Novel Imidazolines and Imidazoles as Selective TAAR1 Partial Agonists for the Treatment of Psychiatric Disorders Giuseppe Cecere, pRED, Discovery Chemistry F. Hoffmann-La Roche AG, Basel, Switzerland Biological Rationale Trace amines are known for four decades Trace Amines - phenylethylamine p- tyramine p- octopamine tryptamine (PEA) Biogenic Amines dopamine norepinephrine serotonin ( DA) (NE) (5-HT) • Structurally related to classical biogenic amine neurotransmitters (DA, NE, 5-HT) • Co-localised & released with biogenic amines in same cells and vesicles • Low concentrations in CNS, rapidly catabolized by monoamine oxidase (MAO) • Dysregulation linked to psychiatric disorders such as schizophrenia & 2 depression Trace Amines Metabolism 3 Biological Rationale Trace Amine-Associated Receptors (TAARs) p-Tyramine extracellular TAAR1 Discrete family of GPCR’s Subtypes TAAR1-TAAR9 known intracellular Gs Structural similarity with the rhodopsin and adrenergic receptor superfamily adenylate Activation of the TAAR1 cyclase receptor leads to cAMP elevation of intracellular cAMP levels • First discovered in 2001 (Borowsky & Bunzow); characterised and classified at Roche in 2004 • Trace amines are endogenous ligands of TAAR1 • TAAR1 is expressed throughout the limbic and monoaminergic system in the brain Borowsky, B. et al., PNAS 2001, 98, 8966; Bunzow, J. R. et al., Mol. Pharmacol. 2001, 60, 1181. Lindemann L, Hoener MC, Trends Pharmacol Sci 2005, 26, 274. 4 Biological Rationale Electrical activity of dopaminergic neurons + p-tyramine -
Differential Regulation of Mecp2 Phosphorylation in the CNS by Dopamine and Serotonin
Neuropsychopharmacology (2012) 37, 321–337 & 2012 American College of Neuropsychopharmacology. All rights reserved 0893-133X/12 www.neuropsychopharmacology.org Differential Regulation of MeCP2 Phosphorylation in the CNS by Dopamine and Serotonin 1 1 2 1,2,3,4 ,1 Ashley N Hutchinson , Jie V Deng , Dipendra K Aryal , William C Wetsel and Anne E West* 1 2 Department of Neurobiology, Duke University Medical Center, Durham, NC, USA; Department of Psychiatry and Behavioral Sciences, Duke 3 University Medical Center, Durham, NC, USA; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, 4 Durham, NC, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC, USA Systemic administration of amphetamine (AMPH) induces phosphorylation of MeCP2 at Ser421 (pMeCP2) in select populations of neurons in the mesolimbocortical brain regions. Because AMPH simultaneously activates multiple monoamine neurotransmitter systems, here we examined the ability of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) to induce pMeCP2. Selective blockade of the DA transporter (DAT) or the 5-HT transporter (SERT), but not the NE transporter (NET), was sufficient to induce pMeCP2 in the CNS. DAT blockade induced pMeCP2 in the prelimbic cortex (PLC) and nucleus accumbens (NAc), whereas SERT blockade induced pMeCP2 only in the NAc. Administration of selective DA and 5-HT receptor agonists was also sufficient to induce pMeCP2; however, the specific combination of DA and 5-HT receptors activated determined the regional- and cell-type specificity of pMeCP2 induction. The D1-class DA receptor agonist SKF81297 induced pMeCP2 widely; however, coadministration of the D2-class agonist quinpirole restricted the induction of pMeCP2 to GABAergic interneurons of the NAc. -
Olfactory Expression of Trace Amine-Associated Receptors
ARTICLE https://doi.org/10.1038/s41467-021-23824-3 OPEN Olfactory expression of trace amine-associated receptors requires cooperative cis-acting enhancers ✉ Ami Shah1,5, Madison Ratkowski1,5, Alessandro Rosa 2,3, Paul Feinstein2,3 & Thomas Bozza 1,4 Olfactory sensory neurons express a large family of odorant receptors (ORs) and a small family of trace amine-associated receptors (TAARs). While both families are subject to so- called singular expression (expression of one allele of one gene), the mechanisms underlying fi 1234567890():,; TAAR gene choice remain obscure. Here, we report the identi cation of two conserved sequence elements in the mouse TAAR cluster (T-elements) that are required for TAAR gene expression. We observed that cell-type-specific expression of a TAAR-derived transgene required either T-element. Moreover, deleting either element reduced or abolished expres- sion of a subset of TAAR genes, while deleting both elements abolished olfactory expression of all TAARs in cis with the mutation. The T-elements exhibit several features of known OR enhancers but also contain highly conserved, unique sequence motifs. Our data demonstrate that TAAR gene expression requires two cooperative cis-acting enhancers and suggest that ORs and TAARs share similar mechanisms of singular expression. 1 Department of Neurobiology, Northwestern University, Evanston, IL, USA. 2 The Graduate Center Programs in Biochemistry, Biology and CUNY Neuroscience Collaborative, New York, NY, USA. 3 Department of Biological Sciences, Hunter College, City University of New York, New York, NY, USA. 4 Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA. 5These authors contributed equally: Ami Shah, Madison Ratkowski. -
Food Sources and Biomolecular Targets of Tyramine
Special Article Food sources and biomolecular targets of tyramine Gaby Andersen, Patrick Marcinek, Nicole Sulzinger, Peter Schieberle, and Dietmar Krautwurst Tyramine is a biogenic trace amine that is generated via the decarboxylation of the amino acid tyrosine. At pico- to nanomolar concentrations, it can influence a multi- tude of physiological mechanisms, exhibiting neuromodulatory properties as well as cardiovascular and immunological effects. In humans, the diet is the primary Downloaded from https://academic.oup.com/nutritionreviews/article/77/2/107/5084469 by guest on 24 September 2021 source of physiologically relevant tyramine concentrations, which are influenced by a large number of intrinsic and extrinsic factors. Among these factors are the avail- ability of tyrosine in food, the presence of tyramine-producing bacteria, the environ- mental pH, and the salt content of food. The process of fermentation provides a particularly good source of tyramine in human nutrition. Here, the potential impact of dietary tyramine on human health was assessed by compiling quantitative data on the tyramine content in a variety of foods and then conducting a brief review of the literature on the physiological, cellular, and systemic effects of tyramine. Together, the data sets presented here may allow both the assessment of tyramine concentrations in food and the extrapolation of these concentrations to gauge the physiological and systemic effects in the context of human nutrition. INTRODUCTION presence of tyramine in a variety of foods, (2) the post- prandial physiological and adverse effects of tyramine, Tyramine is a biogenic amine generated via the decar- and (3) the biomolecular targets of tyramine. It is not boxylation of the amino acid tyrosine in animals, plants, intended to be a systematic or comprehensive review of and microorganisms. -
G Protein-Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. -
G Protein‐Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology (2019) 176, S21–S141 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors Stephen PH Alexander1 , Arthur Christopoulos2 , Anthony P Davenport3 , Eamonn Kelly4, Alistair Mathie5 , John A Peters6 , Emma L Veale5 ,JaneFArmstrong7 , Elena Faccenda7 ,SimonDHarding7 ,AdamJPawson7 , Joanna L Sharman7 , Christopher Southan7 , Jamie A Davies7 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia 3Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK 4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 5Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 6Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 7Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website.