DOCSLIB.ORG

TAAR1 Induces a Disturbed GSK3 Β Phosphorylation in Recurrent

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
TAAR1 Induces a Disturbed GSK3 Β Phosphorylation in Recurrent ID: 17-0272 7 2 S Stavrou et al. TAAR1 upregulation in 7:2 372–384 recurrent miscarriages RESEARCH TAAR1 induces a disturbed GSK3β phosphorylation in recurrent miscarriages through the ODC Stavroula Stavrou1, Michael Gratz1, Eileen Tremmel1, Christina Kuhn1, Simone Hofmann1, Helene Heidegger1, Mina Peryanova1, Kerstin Hermelink1, Stefan Hutter1, Bettina Toth2, Doris Mayr3, Sven Mahner1, Udo Jeschke1 and Aurelia Vattai1 1Department of Gynecology and Obstetrics, Hospital of the LMU, Munich, Germany 2Department of Gynaecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Innsbruck, Austria 3Department of Pathology, Hospital of the LMU, Munich, Germany Correspondence should be addressed to U Jeschke: [email protected] Abstract Objectives: Thyroid hormones play an important role in the maintenance of pregnancy. Key Words Their derivates, endogenous amines, act via binding to the trace amine-associated f TAAR1 receptor (TAAR1). The aim of our study was to analyse the regulation of TAAR1, f pGSK3β serine/threonine kinase (pGSK3β) and ornithine decarboxylase (ODC) in placentas f ODC of healthy pregnancies, spontaneous (SM) and recurrent miscarriages (RM) and to f 3-iodothyronamine investigate the influence of thyroid hormone derivates on TAAR1 expression in f RO5203548 trophoblast model cells in vitro. f spontaneous miscarriages Methods: Patients with SM (n = 15) and RM (n = 15) were compared with patients with f recurrent miscarriages healthy pregnancies (n = 15) (pregnancy weeks 7–13 each). Immunohistochemistry was applied to analyse placental TAAR1, pGSK3β and ODC expression. Protein expression of the receptors after stimulation with T3, T1AM and RO5203548 in BeWo trophoblast model cells was determined via Western blot. Double-immunofluorescence was used to determine placental expression of TAAR1 and ODC. Results: Levels of TAAR1, pGSK3β and ODC were higher in placentas of RM in comparison to healthy controls. Stimulation of BeWo cells with T3, T1AM and RO5203548 significantly increased TAAR1 expression. ODC expression in BeWo cells was upregulated through T3. Via double-immunofluorescence, TAAR1 and ODC-positive EVT could be detected. Conclusions: Upregulation of placental TAAR1 may indicate an increased decarboxylation of thyroid hormones in miscarriages. Patients with RM may have a lack of T3 through an enhanced transformation of T3 into T1AM induced by the ODC. Future investigations could be carried out to analyse what role a prophylactic T3 substitution Endocrine Connections plays for patients. (2018) 7, 372–384 Introduction Thyroid disorders such as hypothyroidism and pregnancy (2). Thyroid hormones, which bind to the hyperthyroidism are associated with increased miscarriage thyroid hormone receptor (THR), play an important role and stillbirth rates (1). Untreated hypothyroidism can during trophoblast differentiation and the development result in a twofold increase of miscarriages; therefore, the of the foetal nervous system (3). THR belongs to the maintenance of an euthyroid state is crucial for a healthy nuclear receptor superfamily, and it is involved in various http://www.endocrineconnections.org © 2018 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-17-0272 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 12/02/2019 12:53:47PM via free access 10.1530/EC-17-0272 S Stavrou et al. TAAR1 upregulation in 7:2 373 recurrent miscarriages physiological processes (4). In a former study, we were able In a recent study, we analysed the regulation of to show that mRNA and protein expression of the THR TAAR1 in breast cancer tissue of primary breast cancer isoforms THRα1, THRα2, THRβ1 and THRβ2 are reduced patients and identified that TAAR1 seems to be an in spontaneous and recurrent miscarriages (RM) (5). independent predictor for breast cancer survival (23). The majority of THR seems to be expressed by decidual TAAR1 overexpression (IRS ≥ 6) was associated with a stromal cells (5). significantly longer overall survival (OS) of breast cancer Degradation of thyroid hormones results in the patients (P = 0.02) than reduced TAAR1 expression (IRS < 6) formation of trace amines (TAs), also referred to as during a maximum follow-up of 14 years, demonstrating thyronamines or endogenous amines (6). Transformation that TAAR1 has a favourable effect on OS of early breast of thyroid hormones into TAs is conducted by the enzyme cancer patients (23). ornithine decarboxylase (ODC) through a deiodisation It is speculated that TAAR1 directly or indirectly and a decarboxylation process (7). Thyronamines (3-T1AM, interferes with the β-arrestin2/Akt/GSK3 pathway (24, 25). T0AM) are endogenous compounds, which can possibly be GSK3 is a serine/threonine protein kinase, and it is encoded derived from L-thyroxine (T4) (7). Decarboxylated thyroid by the two genes GSK3A and GSK3B (26). Besides cellular hormones act through rapid actions like rapid lowering of proliferation, migration, glucose regulation and apoptosis, body temperature and heart rate, while classical thyroid the isoform GSK3β is a key enzyme in the wnt-signalling hormones act epigenetically (8). Ornithine decarboxylase pathways (27). Those are a group of signal transduction (ODC) is a rate-limiting enzyme for the biosynthesis of pathways that play an important role in carcinogenesis and polyamines, and it is responsible for the decarboxylation embryo development. The latter is controlled through cell of thyroid hormones (9, 10). Changes in the brain proliferation and cell migration, and wnt pathways regulate ODC/polyamine system can have an influence on the pre-implantation, blastocyst implantation and uterine development of catecholaminergic nerve pathways (11). decidualisation (27). Wnt-signalling proteins participate Bulgaroni and colleagues found that ODC upregulation in numerous developmental events during embryogenesis may be linked to cytotrophoblast proliferation and and differentiation of diverse reproductive tissues (28, 29). placental repair in compensation to injuries induced by A crosstalk between TAAR1 and dopamine D2L organophosphate pesticides (12). receptor (D2R) has formerly been described (6, 30, 31). Thyroid hormone derivates function by binding to Harmeier and colleagues found that the activation of the G-protein-coupled receptor trace amine-associated the TAAR1-D2R complex negatively modulates GSK3β receptor 1 (TAAR1) (8). TAAR1 was first described in 2001 signalling in vitro and in vivo. D2R is a target receptor for by Borowsky and coworkers (13). Upon activation of various antipsychotic drugs, and TAAR1 can interact with adenylcyclase, TAAR1 induces a rise of the intracellular D2R forming a functional heteromer (6, 32). cAMP level (13, 14). TAAR1 is expressed by the placenta, Aim of our study was to investigate the placental brain, spinal cord, stomach, pancreatic β-cells and immune expression of TAAR1, GSK3β and ODC in healthy cells like macrophages, leukocytes and dendritic cells (15, pregnancies and spontaneous as well as RM and to 16, 17). Different compounds, including dopaminergic, further analyse the crosstalk between these receptors. adrenergic and serotonergic classes and a wide spectrum of Additionally, the influence of TAAR1 ligands on the agonists, such as trace amines, common biogenic amines, expression of TAAR1 in trophoblast model cells in vitro amphetamine-like stimulants and 3-iodothyronamine was assessed. As we assume that the processing of thyroid can activate TAAR1 (18, 19, 20). The only known TAAR1 hormones through the ODC plays an important role antagonist to date is RO5212773 (EPPTB) (21). during miscarriages, regulation of the ODC was a further TAAR1 has so far been investigated in the field of component of the study. neuroscience whereby it could be shown that TAAR1 is able to modulate the serotonergic and dopaminergic system in the brain (15). As TAAR1 is a negative regulator Materials and methods of dopamine transmission, TAAR1 and its agonists as well Tissue samples as antagonists represent a target for psychiatric disorders like Parkinson’s disease, depression and schizophrenia Samples collected from spontaneous (SM, 15 cases) and (15). Stimulation of TAAR1 can furthermore have a RM, 15 cases) in the time period between 2011 and 2012 beneficial effect on glucose and obesity control in mice were obtained from the archives of the Gynaecology with type 2 diabetes mellitus (22). and Obstetrics Department of the Ludwig-Maximilians- http://www.endocrineconnections.org © 2018 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-17-0272 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 12/02/2019 12:53:47PM via free access S Stavrou et al. TAAR1 upregulation in 7:2 374 recurrent miscarriages University Munich, Germany. Samples from elective Immunohistochemistry terminations of pregnancy (ETP, 15 cases) collected in After tissue preparation, tissue samples were fixed in 3.7% the same time period were provided by outpatients clinic formalin and then embedded in paraffin. Formalin-fixed in Munich. Tissue samples were attained by curettage paraffin-embedded sections (3 µm) were deparaffinised without any prior pharmacological induction. In cases in Roticlear (Carl Roth, Karlsruhe, Germany), blocked of miscarriages, curettages were performed within and rehydrated with 3% H O /methanol for
Load more

Recommended publications
  • 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.
    [Show full text]
  • Certificate of Analysis
    Print Date: Jan 3rd 2020 Certificate of Analysis www.tocris.com Product Name: EPPTB Catalog No.: 4518 Batch No.: 1 CAS Number: 1110781-88-8 IUPAC Name: N-(3-Ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide 1. PHYSICAL AND CHEMICAL PROPERTIES Batch Molecular Formula: C20H21F3N2O2 Batch Molecular Weight: 378.39 Physical Appearance: White solid Solubility: DMSO to 100 mM ethanol to 100 mM Storage: Store at +4°C Batch Molecular Structure: 2. ANALYTICAL DATA TLC: Rf = 0.2 (Ethyl acetate:Petroleum ether [4:1]) HPLC: Shows 99.9% purity 1H NMR: Consistent with structure Mass Spectrum: Consistent with structure Microanalysis: Carbon Hydrogen Nitrogen Theoretical 63.48 5.59 7.4 Found 63.37 5.53 7.44 Caution - Not Fully Tested • Research Use Only • Not For Human or Veterinary Use bio-techne.com North America China Europe Middle East Africa Rest of World [email protected] Tel: (800) 343 7475 [email protected] Tel: +44 (0)1235 529449 www.tocris.com/distributors [email protected] Tel: +86 (21) 52380373 Tel:+1 612 379 2956 Print Date: Jan 3rd 2020 Product Information www.tocris.com Product Name: EPPTB Catalog No.: 4518 Batch No.: 1 CAS Number: 1110781-88-8 IUPAC Name: N-(3-Ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide Description: Storage: Store at +4°C Trace amine 1 (TA ) receptor antagonist/inverse agonist; 1 Solubility & Usage Info: exhibits a higher potency at the mouse TA1 receptor than the rat DMSO to 100 mM and human TA150 receptors (IC values are 27.5, 4539 and 7487 ethanol to 100 mM nM, respectively).
    [Show full text]
  • Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, L-DOPA Responsivity, and Glutamatergic Neurotransmission
    The Journal of Neuroscience, October 14, 2015 • 35(41):14057–14069 • 14057 Neurobiology of Disease Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, L-DOPA Responsivity, and Glutamatergic Neurotransmission Alexandra Alvarsson,1* Xiaoqun Zhang,1* Tiberiu L Stan,1 Nicoletta Schintu,1 Banafsheh Kadkhodaei,2 Mark J. Millan,3 Thomas Perlmann,2,4 and Per Svenningsson1 1Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden, 2Ludwig Institute for Cancer Research, SE-17177 Stockholm, Sweden, 3Pole of Innovation in Neuropsychiatry, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris 87290, France, and 4Department of Cell and Molecular Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden Parkinson’s disease (PD) is a movement disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Restoration of dopamine transmission by L-DOPA relieves symptoms of PD but causes dyskinesia. Trace Amine-Associated Receptor 1 (TAAR1) modulates dopaminergic transmission, but its role in experimental Parkinsonism and L-DOPA responses has been neglected. Here, we report that TAAR1 knock-out (KO) mice show a reduced loss of dopaminergic markers in response to intrastriatal 6-OHDA administra- tion compared with wild-type (WT) littermates. In contrast, the TAAR1 agonist RO5166017 aggravated degeneration induced by intra- striatal6-OHDAinWTmice.Subchronic L-DOPAtreatmentofTAAR1KOmiceunilaterallylesionedwith6-OHDAinthemedialforebrain bundle resulted in more pronounced rotational behavior and dyskinesia than in their WT counterparts. The enhanced behavioral sensitization to L-DOPA in TAAR1 KO mice was paralleled by increased phosphorylation of striatal GluA1 subunits of AMPA receptors. Conversely, RO5166017 counteracted both L-DOPA-induced rotation and dyskinesia as well as AMPA receptor phosphorylation.
    [Show full text]
  • 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.
    [Show full text]
  • Update on 3-Iodothyronamine and Its Neurological and Metabolic Actions
    REVIEW ARTICLE published: 16 October 2014 doi: 10.3389/fphys.2014.00402 Update on 3-iodothyronamine and its neurological and metabolic actions Riccardo Zucchi*, Alice Accorroni and Grazia Chiellini Laboratory of Biochemistry, Department of Pathology, University of Pisa, Pisa, Italy Edited by: 3-iodothyronamine (T1AM) is an endogenous amine, that has been detected in many Maria Moreno, University of Sannio, rodent tissues, and in human blood. It has been hypothesized to derive from thyroid Italy hormone metabolism, but this hypothesis still requires validation. T1AM is not a Reviewed by: ligand for nuclear thyroid hormone receptors, but stimulates with nanomolar affinity Anna M. D. Watson, Baker IDI Heart and Diabetes Institute, Australia trace amine-associated receptor 1 (TAAR1), a G protein-coupled membrane receptor. Carolin Stephanie Hoefig, Karolinska With a lower affinity it interacts with alpha2A adrenergic receptors. Additional targets Institutet, Sweden are represented by apolipoprotein B100, mitochondrial ATP synthase, and membrane *Correspondence: monoamine transporters, but the functional relevance of these interactions is still Riccardo Zucchi, Laboratory of uncertain. Among the effects reported after administration of exogenous T1AM to Biochemistry, Department of Pathology, University of Pisa, Via experimental animals, metabolic and neurological responses deserve special attention, Roma 55, 56126 Pisa, Italy because they were obtained at low dosages, which increased endogenous tissue e-mail: [email protected] concentration by about one order of magnitude. Systemic T1AM administration favored fatty acid over glucose catabolism, increased ketogenesis and increased blood glucose. Similar responses were elicited by intracerebral infusion, which inhibited insulin secretion and stimulated glucagon secretion. However, T1AM administration increased ketogenesis and gluconeogenesis also in hepatic cell lines and in perfused liver preparations, providing evidence for a peripheral action, as well.
    [Show full text]
  • The Involvement of Trace Amine-Associated Receptor 1 and Thyroid Hormone Transporters in Non-Classical Pathways of the Thyroid Gland Auto-Regulation
    The Involvement of Trace Amine-Associated Receptor 1 and Thyroid Hormone Transporters in Non-Classical Pathways of the Thyroid Gland Auto-Regulation by Maria Qatato a Thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Cell Biology Approved Dissertation Committee Prof. Dr. Klaudia Brix Jacobs University Bremen Prof. Sebastian Springer, DPhil Jacobs University Bremen Dr. Georg Homuth Ernst-Moritz-Arndt-Universität Greifswald Date of Defence: 16 January 2018 Department of Life Sciences and Chemistry Statutory Declaration Family Name, Given/First Name Qatato, Maria Matriculation number 20330110 What kind of thesis are you submitting: PhD Thesis English: Declaration of Authorship I hereby declare that the thesis submitted was created and written solely by myself without any external support. Any sources, direct or indirect, are marked as such. I am aware of the fact that the contents of the thesis in digital form may be revised with regard to usage of unauthorized aid as well as whether the whole or parts of it may be identified as plagiarism. I do agree my work to be entered into a database for it to be compared with existing sources, where it will remain in order to enable further comparisons with future theses. This does not grant any rights of reproduction and usage, however. This document was neither presented to any other examination board nor has it been published. German: Erklärung der Autorenschaft (Urheberschaft) Ich erkläre hiermit, dass die vorliegende Arbeit ohne fremde Hilfe ausschließlich von mir erstellt und geschrieben worden ist. Jedwede verwendeten Quellen, direkter oder indirekter Art, sind als solche kenntlich gemacht worden.
    [Show full text]
  • The Selective Antagonist EPPTB Reveals TAAR1-Mediated Regulatory Mechanisms in Dopaminergic Neurons of the Mesolimbic System
    The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system Amyaouch Bradaiaa,b, Gerhard Trubec, Henri Stalderc, Roger D. Norcrossc, Laurence Ozmenc, Joseph G. Wettsteinc, Audre´ e Pinarda, Danie` le Buchyc, Martin Gassmanna, Marius C. Hoenerc, and Bernhard Bettlera,1 aDepartment of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, CH-4056 Basel, Switzerland; bNeuroservice, 13593 Aix en Provence, Cedex 03, France; and cPharmaceuticals Division, Neuroscience Research, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland Edited by Shigetada Nakanishi, Osaka Bioscience Institute, Osaka, Japan, and approved September 29, 2009 (received for review June 11, 2009) Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor-mediated pathway. The genetic absence of TAAR1 receptor (GPCR) that is nonselectively activated by endogenous clearly increased the spontaneous firing rate of DA neurons but metabolites of amino acids. TAAR1 is considered a promising drug the underlying signaling mechanism remained unclear (7). Taar1 target for the treatment of psychiatric and neurodegenerative knockout mice also display behavioral and neurochemical signs disorders. However, no selective ligand to identify TAAR1-specific of DA supersensitivity, a feature thought to relate to positive signaling mechanisms is available yet. Here we report a selective symptoms of schizophrenia (8). In addition, TAs were implicated TAAR1 antagonist, EPPTB, and characterize its physiological effects in the etiology of depression, addiction, attention-deficit/ at dopamine (DA) neurons of the ventral tegmental area (VTA). We hyperactivity disorder, and Parkinson’s disease (5, 9, 10). How- show that EPPTB prevents the reduction of the firing frequency of ever, validation of therapeutic concepts was hampered by the DA neurons induced by p-tyramine (p-tyr), a nonselective TAAR1 lack of a ligand that specifically regulates TAAR1 activity in agonist.
    [Show full text]
  • SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action S
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2019/08/01/jpet.119.260281.DC1 1521-0103/371/1/1–14$35.00 https://doi.org/10.1124/jpet.119.260281 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 371:1–14, October 2019 Copyright ª 2019 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action s Nina Dedic,1 Philip G. Jones,1 Seth C. Hopkins, Robert Lew, Liming Shao, John E. Campbell, Kerry L. Spear, Thomas H. Large, Una C. Campbell, Taleen Hanania, Emer Leahy, and Kenneth S. Koblan Sunovion Pharmaceuticals, Marlborough, Massachusetts (N.D., P.G.J., S.C.H., R.L., L.S., J.E.C., K.L.S., T.H.L., U.C.C., K.S.K.); and PsychoGenics, Paramus, New Jersey (T.H., E.L.) Received May 24, 2019; accepted July 10, 2019 Downloaded from ABSTRACT For the past 50 years, the clinical efficacy of antipsychotic amine-associated receptor 1 and 5-HT1A receptors is integral to medications has relied on blockade of dopamine D2 receptors. its efficacy. Based on the preclinical data and its unique Drug development of non-D2 compounds, seeking to avoid mechanism of action, SEP-856 is a promising new agent for the limiting side effects of dopamine receptor blockade, has the treatment of schizophrenia and represents a new pharma- jpet.aspetjournals.org failed to date to yield new medicines for patients.
    [Show full text]
  • TAAR1) Agonist RO5263397
    fphar-09-00645 June 20, 2018 Time: 17:0 # 1 ORIGINAL RESEARCH published: 21 June 2018 doi: 10.3389/fphar.2018.00645 Biochemical and Functional Characterization of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist RO5263397 Stefano Espinoza1, Damiana Leo1,2, Tatyana D. Sotnikova3, Mohammed Shahid4, Tiina M. Kääriäinen5 and Raul R. Gainetdinov3,6* 1 Fondazione Istituto Italiano di Tecnologia, Department of Neuroscience and Brain Technologies, Genoa, Italy, 2 Department of Neurosciences, University of Mons, Mons, Belgium, 3 Institute of Translational Biomedicine, Saint Petersburg State University, Saint Petersburg, Russia, 4 Orion Pharma, Nottingham, United Kingdom, 5 Orion Pharma, Turku, Finland, 6 Skolkovo Institute of Science and Technology, Moscow, Russia Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor, which signals through elevating intracellular cAMP levels, and expressed in most vertebrates, including rodents and humans. In recent years, several lines of evidence indicated Edited by: the role of TAAR1 in the regulation of dopaminergic system and its importance in Pascal Bonaventure, Janssen Research & Development, physiological processes such as locomotion, control of emotional states and cognition. United States In our study, we used RO5263397, a selective TAAR1 agonist, as a tool and Reviewed by: characterized its pharmacology in vitro in HEK293 cells and its effects in vivo in Jun-Xu Li, University at Buffalo, United States tests assessing potential antidepressant and antipsychotic actions. We found that Heike Biebermann, RO5263397 not only increases cAMP levels at very low concentrations but also Charité Universitätsmedizin Berlin, can induce the phosphorylation of ERK and CREB in a concentration- and time- Germany Pietro Cottone, dependent manner.
    [Show full text]
  • Trace Amine Receptor (Version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
    IUPHAR/BPS Guide to Pharmacology CITE https://doi.org/10.2218/gtopdb/F64/2019.4 Trace amine receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database Tom I. Bonner1, Anthony P. Davenport2, Stephen M. Foord3, Janet J. Maguire2 and William A.E. Parker2 1. National Institute of Mental Health, USA 2. University of Cambridge, UK 3. GlaxoSmithKline, UK Abstract Trace amine-associated receptors were discovered from a search for novel 5-HT receptors [9], where 15 mammalian orthologues were identified and divided into two families. The TA1 receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Trace amine receptor [53]) has affinity for the endogenous trace amines tyramine, β-phenylethylamine and octopamine in addition to the classical amine dopamine [9]. Emerging evidence suggests that TA1 is a modulator of monoaminergic activity in the brain 9[ 0] with TA1 and dopamine D2 receptors shown to form constitutive heterodimers when co-expressed 2[ 8]. In addition to trace amines, receptors can be activated by amphetamine-like psychostimulants, and endogenous thyronamines. Contents This is a citation summary for Trace amine receptor in the Guide to Pharmacology database (GtoPdb). It exists purely as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analyzers. Readers will almost certainly want to visit the relevant sections of the database which are given here under database links. GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database.
    [Show full text]
  • 3-Iodothyronamine Affects Thermogenic Substrates' Mobilization in Brown Adipocytes
    biology Article 3-Iodothyronamine Affects Thermogenic Substrates’ Mobilization in Brown Adipocytes Manuela Gencarelli 1, Annunziatina Laurino 1, Elisa Landucci 2, Daniela Buonvicino 2, Costanza Mazzantini 2, Grazia Chiellini 3 and Laura Raimondi 1,* 1 Department of Neuroscience, Psychology, Drug Sciences, and Child Health (NEUROFARBA), University of Florence, 50139 Florence, Italy; manuela.gencarelli@unifi.it (M.G.); annunziatina.laurino@unifi.it (A.L.) 2 Department of Health Sciences, Section of Pharmacology, University of Florence, 50139 Florence, Italy; elisa.landucci@unifi.it (E.L.); daniela.buonvicino@unifi.it (D.B.); costanza.mazzantini@unifi.it (C.M.) 3 Department of Pathology, University of Pisa, 50123 Pisa, Italy; [email protected] * Correspondence: laura.raimondi@unifi.it; Tel.: +390-554-278-375 Received: 2 April 2020; Accepted: 27 April 2020; Published: 4 May 2020 Abstract: We investigated the effect of 3-iodothyronamine (T1AM) on thermogenic substrates in brown adipocytes (BAs). BAs isolated from the stromal fraction of rat brown adipose tissue were exposed to an adipogenic medium containing insulin in the absence (M) or in the presence of 20 nM T1AM (M+T1AM) for 6 days. At the end of the treatment, the expression of p-PKA/PKA, p-AKT/AKT, p-AMPK/AMPK, p-CREB/CREB, p-P38/P38, type 1 and 3 beta adrenergic receptors (β1–β3AR), GLUT4, type 2 deiodinase (DIO2), and uncoupling protein 1 (UCP-1) were evaluated. The effects of cell conditioning with T1AM on fatty acid mobilization (basal and adrenergic-mediated), glucose uptake (basal and insulin-mediated), and ATP cell content were also analyzed in both cell populations.
    [Show full text]
  • Differential Mechanisms of Action of the Trace Amines Octopamine
    www.nature.com/scientificreports OPEN Diferential mechanisms of action of the trace amines octopamine, synephrine and tyramine on the Received: 15 March 2019 Accepted: 29 June 2019 porcine coronary and mesenteric Published: xx xx xxxx artery Andy Hsien Wei Koh 1, Russ Chess-Williams1,2 & Anna Elizabeth Lohning1 Trace amines such as p-tyramine, p-octopamine and p-synephrine are found in low concentrations in animals and plants. Consumption of pre-workout supplements containing these plant-derived amines has been associated with cardiovascular side efects. The aim of this study was to determine the mechanisms of action of these trace amines on porcine isolated coronary and mesenteric arteries. Noradrenaline caused contraction of mesenteric arteries and relaxation of coronary arteries. In both tissues, all three trace amines induced contractions with similar potencies and responses were unafected by the β-adrenoceptor antagonist propranolol (1 µM), the nitric oxide synthase inhibitor L-NNA (100 µM), or the TAAR-1 antagonist, EPPTB (100 nM). However, the contractile responses of mesenteric arteries, but not coronary arteries, were signifcantly reduced by depletion of endogenous noradrenaline. Mesenteric responses to all three amines were abolished in the presence of prazosin (1 µM) whereas residual contractile responses remained in the coronary artery which were inhibited by a high concentration (100 µM) of EPPTB. The results suggest complex responses of the coronary artery to the trace amines, with activity at α1-adrenoceptors and potentially TAARs other than TAAR-1. In contrast the actions of the amines on the mesenteric artery appeared to involve indirect sympathomimetic actions and direct actions on α1-adrenoceptors.
    [Show full text]