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Proquest Dissertations NOTE TO USERS This reproduction is the best copy available. UMI* mn u Ottawa L'Universite canadienne Canada's university ITTTT FACULTE DES ETUDES SUPERIEURES L^=l FACULTY OF GRADUATE AND ET POSTDOCTORALES U Ottawa POSTDOCTORAL STUDIES i.'Universiti'; ciimidienne Canada's university Jean-Philippe D'Aoust AUTEUR DE LA THESE / AUTHOR OF THESIS M.Sc. (Neuroscience) GRADE/DEGREE Department of Cellular and Molecular Medicine 'FACULTETCOLETDEPA!™ Identifying the Roles of the Amino Terminal and first Transmembrane Regions of Human Dl-like Dopaminergic Receptors Using Mutagenesis TITRE DE LA THESE / TITLE OF THESIS M. Tiberi DIRECTEUR (DIRECTRICE) DE LA THESE / THESIS SUPERVISOR CO-DIRECTEUR (CO-DIRECTRICE) DE LA THESE / THESIS CO-SUPERVISOR EXAMINATEURS (EXAMINATRICES) DE LA THESE/THESIS EXAMINERS P. Albert J. Da Silva Gary W. Slater Le Doyen de la Faculte des etudes superieures et postdoctorales / Dean of the Faculty of Graduate and Postdoctoral Studies IDENTIFYING THE ROLES OF THE AMINO TERMINAL AND FIRST TRANSMEMBRANE REGIONS OF HUMAN DL-LIKE DOPAMINERGIC RECEPTORS USING MUTAGENESIS by JEAN-PHILIPPE D'AOUST This thesis is submitted as a partial fulfillment of the M.Sc. program in Neuroscience June 2009 Department of Cellular and Molecular Medicine Faculty of Medicine University of Ottawa © Jean-Philippe D'Aoust, Ottawa, Ontario, Canada, June 2009 Library and Archives Bibliotheque et 1*1 Canada Archives Canada Published Heritage Direction du Branch Patrimoine de Pedition 395 Wellington Street 395, rue Wellington Ottawa ON MAOISM OttawaONK1A0N4 Canada Canada Your file Votre reference ISBN: 978-0-494-59466-7 Our file Notre reference ISBN: 978-0-494-59466-7 NOTICE: AVIS: The author has granted a non­ L'auteur a accorde une licence non exclusive exclusive license allowing Library and permettant a la Bibliotheque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par telecommunication ou par I'lntemet, preter, telecommunication or on the Internet, distribuer et vendre des theses partout dans le loan, distribute and sell theses monde, a des fins commerciales ou autres, sur worldwide, for commercial or non­ support microforme, papier, electronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriete du droit d'auteur ownership and moral rights in this et des droits moraux qui protege cette these. Ni thesis. Neither the thesis nor la these ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent etre imprimes ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author's permission. In compliance with the Canadian Conformement a la loi canadienne sur la Privacy Act some supporting forms protection de la vie privee, quelques may have been removed from this formulaires secondaires ont ete enleves de thesis. cette these. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n'y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. ••• Canada Abstract Although Dl-like dopaminergic receptors (D1R and D5R) share similar primary sequences, they possess distinct ligand binding and G protein-coupling properties. Since no ligands discriminate the closely related D1R and D5R, the discovery of their subtype- specific functional and physiological functions is stalled. To provide additional conformational data about the binding pocket of Dl-like receptors, we assessed the functional roles of their highly divergent amino terminal cassette. Using a chimerical approach, we swapped the extracellular amino terminal (NT) and first transmembrane (TM1) regions of human Dl-like receptors and found that both regions distinctly control dopamine efficacy. Furthermore, chimeras with a swapped TM1 domain have altered affinity and selectivity properties. We further identified two residues in TM1 controlling ligand binding while one of them is also crucial for dopamine efficacy. Our present results highlight structural and functional roles of TM1 and NT of human Dl-like dopaminergic receptors. u Table of contents ABSTRACT II TABLE OF CONTENTS Ill LIST OF TABLES V CHAPTER 2. MANUSCRIPT #1 v CHAPTER 3. MANUSCRIPT #2 v LIST OF FIGURES VI CHAPTER 1. INTRODUCTION vi CHAPTER 2. MANUSCRIPT #1 vi CHAPTER 3. MANUSCRIPT #2 vn CHAPTER 4. GENERAL DISCUSSION vm CHAPTER 6. APPENDICES vm LIST OF ABBREVIATIONS IX ACKNOWLEDGMENTS XII CHAPTER 1. INTRODUCTION 1 1.1 THE BASIC PRINCIPLES OF DOPAMINE NEUROTRANSMISSION 2 1.1.1 Neurotransmitter synthesis, storage and release 2 1.1.2 The family of dopamine receptors 3 1.1.3 The nigrostriatal pathway and Parkinson's disease 7 1.1.4 The mesocortical and mesolimbic pathways and schizophrenia 9 1.1.5 The hypothalamo-pituitary pathway 10 1.1.6 Roles of dopamine outside the central nervous system 11 1.2 CRYSTALLOGRAPHIC STUDIES OF G PROTEIN-COUPLED RECEPTORS 12 1.2.1 Rhodopsin, the first crystallized GPCR 12 1.2.2 Problems with the crystallization other GPCRs and their resolution 15 1.2.3 Differences between the new three-dimensional structures of mutant GPCRs and rhodopsin 17 1.3 REGULATION OF G PROTEIN-COUPLED RECEPTOR FUNCTIONS 19 1.3.1 Families of G protein-coupled receptors under the GRAFS system 19 1.3.2 The heterotrimeric G proteins and their effectors 21 1.3.3 Receptor trafficking, from the endoplasmic reticulum to lysosomes 27 1.4 THE DOPAMINE Dl-LIKE RECEPTOR SUB-FAMILY 32 1.4.1 Polymorphisms occurring in Dl-like receptors 32 1.4.2 Characteristics of the Dl-like receptor sub-family 33 1.4.3 The distribution of Dl-like dopamine receptors, in brain and in periphery... 37 1.4.4 What have we learned from Dl-like receptor knockout mice models? 40 1.4.5 The binding pocket of dopamine Dl receptor 43 1.4.6 Elucidating the functional properties of structural components of Dl-like receptors 45 1.5 ISSUES, HYPOTHESES AND OBJECTIVES 48 iii CHAPTER 2. MANUSCRIPT #1 51 CHAPTER 3. MANUSCRIPT #2 97 CHAPTER 4. GENERAL DISCUSSION 142 4.1 THE AMINO TERMINAL CASSETTE OF D1-LIKE RECEPTORS 143 4.2 CHEMICAL STRUCTURES AND RECEPTOR ACTIVATION: IS THERE A LINK? 144 4.3 COOPERATION OF RESIDUES WITHIN THE TM1 HELIX 148 4.4 SEQUENTIAL BINDING OF LIGANDS 151 4.5 A POSSIBLE CHOLESTEROL BINDING RESIDUE 153 4.6 UNSOLVED QUESTIONS 155 4.7 CLOSING REMARKS 156 CHAPTER 5. REFERENCES 158 CHAPTER 6. APPENDICES 177 iv List of tables Chapter 2. Manuscript #1 Table I. Dissociation constants (Kd) and maximal binding capacity (Bmax) values of N- [methyl-3H]-SCH23390 for wild type and chimerical Dl-like receptors 64 Table II. Inhibitory dissociation constants (Kj) values of dopaminergic ligands for wild type and chimerical Dl-like receptors 67 Table III. Inhibitory dissociation constants (Kj) values of dopaminergic ligands for wild type and TM1-swapped Dl-like receptors 71 Table SI. List of custom PCR primers 93 Chapter 3. Manuscript #2 Table I. Dissociation constants (Kd) and maximal binding capacity (Bmax) values of N- [methyl-3H]-SCH23390 for wild type and multiple point mutant Dl-like receptors Ill Table II. Inhibitory dissociation constants (Kj) values of dopamine and benzazepine ligands for wild type and multiple point mutant Dl-like receptors 113 Table III. Inhibitory dissociation constants (Kj) values of antipsychotic drug for wild type and multiple point mutant Dl-like receptors 114 Table IV. Dissociation constants (Kd) and maximal binding capacity (Bmax) values of N- [methyl-3H]-SCH23390 for wild type and single point mutant Dl-like receptors 117 Table V. Inhibitory dissociation constants (Kj) values of dopaminergic ligands for wild type and single point mutant Dl-like receptors 119 Table SI. List of custom PCR primers 138 v List of figures Chapter 1. Introduction Figure I. Synthesis, storage, release and reuptake of dopamine 4 Figure II. Schematic representation of a G protein-coupled receptor 6 Figure III. Three-dimensional structure of rhodopsin, a GPCR 14 Figure IV. Activation and signal termination of heterotrimeric G proteins 22 Figure V. The cAMP-PKA signaling pathway 24 Figure VI. Trafficking of G protein-coupled receptors following activation 30 Figure VII. Topology of human Dl-like dopaminergic receptors 34 Figure VIII. DARPP-32 signaling cascade 36 Chapter 2. Manuscript #1 Figure 1. Primary sequence of the extracellular amino terminus (NT) and first transmembrane domain (TM1) of the human Dl-like receptors and schematic representation of wild type and chimerical receptors 63 Figure 2. Affinity change (in %) of dopaminergic ligands for chimerical receptors relative to parent wild type receptor 68 Figure 3. Selectivity ratios of dopaminergic ligands for wild type and chimerical Dl-like receptors 70 Figure 4. Affinity change (in %) of dopaminergic ligands for TM1-swapped receptors relative to parent wild type receptor 72 vi Figure 5. Selectivity ratios of dopaminergic ligands for wild type and TM1 -swapped Dl- like receptors 73 Figure 6. Agonist-independent activity of wild type and chimerical Dl-like receptors expressed in HEK293 cells 76 Figure 7. DA-mediated stimulation of adenylyl cyclase activity by wild type and chimerical Dl-like receptors expressed in HEK293 cells 77 Figure 8. Basal activity of antipsychotics on HEK293 cells expressing wild type or TM1- swapped Dl-like receptors 79 Figure 9. Activity of dopaminergic agonists on HEK293 cells expressing wild type or TMl-swapped Dl-like receptors 82 Figure SI. Chemical structures of dopamine and benzazepine ligands 95 Figure S2. Chemical structures of antipsychotic drugs 96 Chapter 3. Manuscript #2 Figure 1. Primary sequence of the first transmembrane domain (TM1) of human Dl-like receptors and schematic representation of wild type and mutant receptors 110 Figure 2. Affinity change (in %) of dopaminergic ligands for multiple point mutant receptors relative to parent wild type receptor 115 Figure 3.
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