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Reverse Transport of the Dopamine Transporter in Neuropsychiatric Disease: Mechanisms of Regulation and Dysfunction

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Reverse Transport of the Dopamine Transporter in Neuropsychiatric Disease: Mechanisms of Regulation and Dysfunction REVERSE TRANSPORT OF THE DOPAMINE TRANSPORTER IN NEUROPSYCHIATRIC DISEASE: MECHANISMS OF REGULATION AND DYSFUNCTION By Andrea N. Belovich Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmacology May, 2017 Nashville, Tennessee Approved: Eugenia Gurevich, Ph.D. Hassane Mchaourab, Ph.D. Brad Grueter, Ph.D. Seth Bordenstein, Ph.D. Aurelio Galli, Ph.D. Dedicated to my parents, Richard and Laura, and to my brother, Reisto. You have always believed in me. ii ACKNOWLEDGMENTS One of the most inspiring discoveries I have made during my doctoral education is the joy that comes from working as part of a community of passionate, dedicated, and visionary scientists and educators. When I imagine what my life would have been like for the past few years without the support of this community, I can only conclude that my pre-doctoral training would have been decidedly more challenging and infinitely less rewarding. There are too many members of this community (past and present) to list and thank individually, but the following people deserve special recognition for their role in guiding me through the process of becoming a Ph.D. I would first like to thank my thesis committee, Eugenia Gurevich, Brad Grueter, Seth Bordenstein, Jeremy Veenstra-VanderWeele, and Hassane Mchaourab, for helping to shape my professional growth and development. Their encouragement has meant the world to me. I also wish to acknowledge the wonderfully unique collection of talent that is the Galli lab, especially Heinrich Matthies, Kevin Erreger, and Christine Saunders. Heiner, Kevin, and Christine are respected colleagues and role models who have provided me with generous scientific and professional training. Nicole Bibus Christianson and Amanda Poe have selflessly given me both their technical and personal guidance, and I am indebted to them for their endless support. I am also immensely grateful to my mentor Aurelio Galli, who has provided me with opportunities to be challenged, to grow, and to develop the confidence necessary to succeed in any challenge that may present itself in the future. Finally, I wish to thank my parents, Richard and Laura Belovich, and my brother Reisto Belovich, who have all been a wellspring of patience, love, and support. No matter how deeply nor how frequently I have drawn from this well, I have never found it to be dry. iii TABLE OF CONTENTS Page DEDICATION ...................................................................................................................... …..….ii ACKNOWLEDGEMENTS... ................................................................................................... .….iii LIST OF TABLES ........................................................................................................................ vi LIST OF FIGURES ..................................................................................................................... vii LIST OF ABBREVIATIONS ......................................................................................................... x Chapter 1. INTRODUCTION ...................................................................................................................... 1 Dopaminergic Circuits .................................................................................................... 1 The Dopaminergic Synapse ........................................................................................... 3 Dopamine Transporter Structure ................................................................................... 7 Dopamine Transporter Function ................................................................................. 12 Reverse Transport: Amphetamine-Induced Dopamine Efflux .................................. 18 Dopamine Transporter Variants and Neuropsychiatric Disease .............................. 26 Studying hDAT-mediated reverse transport of DA .................................................... 35 2. PHOSPHATIDYLINOSITOL (4,5)-BISPHOSPHATE REGULATES PSYCHOSTIMULANT BEHAVIORS THROUGH ITS INTERACTION WITH THE DOPAMINE TRANSPORTER N-TERMINUS ......................................................................................................................... 38 Abstract .......................................................................................................................... 38 Introduction ................................................................................................................... 39 Results ........................................................................................................................... 40 Discussion ..................................................................................................................... 63 Materials and methods ................................................................................................. 67 3. PUTATIVE PHOSPHATIDYLINOSITOL (4,5)-BISPHOSPHATE BINDING SITES ON DOPAMINE TRANSPORTER INTRACELLULAR LOOP REGIONS CONTROL TRANSPORTER FUNCTION ................................................................................................. 76 Introduction ................................................................................................................... 76 Results ........................................................................................................................... 77 Discussion ..................................................................................................................... 80 4. DE NOVO MUTATION IN THE DOPAMINE TRANSPORTER GENE ASSOCIATES DOPAMINE DYSFUNCTION WITH AUTISM SPECTRUM DISORDER ............................... 87 Abstract .......................................................................................................................... 87 Introduction ................................................................................................................... 88 Results ........................................................................................................................... 90 Discussion ................................................................................................................... 100 Materials and methods ............................................................................................... 103 Clinical information ..................................................................................................... 106 iv 5. ZN2+ REVERSES FUNCTIONAL DEFECITS IN A DE NOVO DOPAMINE TRANSPORTER VARIANT ASSOCIATED WITH AUTISM SPECTRUM DISORDER ....... 109 Abstract ........................................................................................................................ 109 Introduction ................................................................................................................. 109 Results ......................................................................................................................... 110 Discussion ................................................................................................................... 113 6. RARE AUTISM-ASSOCIATED VARIANTS IMPLICATE SYNTAXIN 1 (STX1 R26Q) PHOSPHORYLATION AND THE DOPAMINE TRANSPORTER (HDAT R51W) IN DOPAMINE NEUROTRANSMISSION AND BEHAVIORS .................................................. 115 Abstract ........................................................................................................................ 115 Introduction ................................................................................................................. 116 Results ......................................................................................................................... 117 Discussion ................................................................................................................... 136 Materials and methods ............................................................................................... 139 7. FUTURE DIRECTIONS ........................................................................................................ 149 REFERENCES ......................................................................................................................... 155 v LIST OF TABLES Table Page 1. Disease-associated variants and their respective functional phenotypes ..................... 28 2. Infantile Dystonia-associated hDAT mutations and respective in vitro functional phenotypes .......................................................................................................... 33 3. Autism Diagnostic Interview-Revised (ADI-R) algorithm domain scores ...................... 120 vi LIST OF FIGURES Figure Page 1. Schematic of dopaminergic projections in the brain .......................................................... 2 2. Dopamine Synthesis ............................................................................................................... 4 3. Overview of the dopaminergic synapse ............................................................................... 6 4. Enzymatic degradation of DA ................................................................................................ 7 5. hDAT topology map ................................................................................................................ 9 6. Drosophila dopamine transporter (DATcryst) structure .....................................................
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