Identification of a Novel Synaptic G Protein-Coupled Receptor Controlling Nicotine Dependence and Withdrawal

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Identification of a Novel Synaptic G Protein-Coupled Receptor Controlling Nicotine Dependence and Withdrawal Identification of a novel synaptic G protein-coupled receptor controlling nicotine dependence and withdrawal Inaugural-Dissertation to obtain the academic degree Doctor rerum naturalium (Dr. rer. nat.) Submitted to the Department of Biology, Chemistry and Pharmacy of the Freie Universität Berlin by Beatriz Antolin Fontes from Girona, Spain Berlin, March 2014 This work was carried out in the period from June 2010 until March 2014 under the supervision of Dr. Inés Ibañez-Tallon and Prof. Dr. Constance Scharff at the Max- Delbrück-Center for Molecular Medicine (MDC) in Berlin and at The Rockefeller University in New York. 1st Reviewer: Dr. Inés Ibañez-Tallon 2nd Reviewer: Prof. Dr. Constance Scharff Date of defense: 18.06.2014 Scientific Acknowledgments I would like to express my sincere gratitude to all the people who made this thesis possible: - My supervisor Dr. Inés Ibañez-Tallon: For your advice, support and supervision throughout the years. Thank you for believing in me from the first moment, for giving me the opportunity to do research in different outstanding environments and specially, for transmitting always motivation and inspiration. I could not wish for a better supervisor. - My supervisor Prof. Dr. Constance Scharff from the Freie Universität Berlin: For your supervision and advice. - Prof. Dr. Nathaniel Heintz: For your valuable support and for so many useful and constructive recommendations on this project. - My fellow lab members, both current and past: Dr. Silke Frahm-Barske, Dr. Marta Slimak, Dr. Jessica Ables, Dr. Andreas Görlich, Dr. Sebastian Auer, Branka Kampfrath, Cuidong Wang, Syed Shehab, Dr. Martin Laqua, Dr. Julio Santos-Torres, Susanne Wojtke, Monika Schwarz-Harsi, and all Prof. Heintz lab members: For your help, not only in carrying out the research but also in creating such a great social work environment. - Dr. Kunihiro Uryu and Dr. Nadine Soplop: For introducing me to the fascinating world of electron microscopy. Thank you so much for teaching me and helping me, for your advice and patience. It’s been such an enjoyable experience that I am actually considering to work in this field in the future. - Timkehet Teffera: For your invaluable assistance. - The Max Delbrück Center for Molecular Medicine, particularly the International Program MolNeuro and its coordinator Dr. Jana Droese; Freie Universität and The Rockefeller University: For the financial, academic and technical support during these years. - NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD: For providing us with human brain samples. Personal Acknowledgments - To great friends I met in Berlin and New York. Thank you for helping me get through the difficult times, for all the emotional support, friendship, entertainment, and caring you provided. - Als amics/amigues de tota la vida, per ser el que sou, amics de tota la vida. - To Jeff, Josefina and Lola: For making this roommate experience so fun and easy. - A mi família, sobretodo a mis padres y hermanos. Gracias por el apoyo incondicional continuo, por hacerme quien soy, por animarme a dar cada uno de los pasos que necesitaba para empezar y acabar la tesis, por seguirme por la mitad del planeta y venir a visitarme incluso durante las peores tormentas de nieve. Gracias por estar siempre tan cerca y por las incontables horas en Skype. - Al meu amor: First of all, thank you for encouraging me to make a step forward to move to Berlin. Second, thank you Dr. Perrinjaquet for being my personal consultant in western blots, immunoprecipitations and general molecular biology. Thank you for listening to all my Gpr151 stories and for giving me great advice. I el més important de tot, moltíssimes gràcies per haver-te casat amb mi dues vegades i voler casar-te amb mi moltes vegades més. Contents 5 Contents 1. INTRODUCTION ............................................................................................ 8 1.1 The habenular nucleus and its output to the midbrain ........................................ 8 1.1.1 Medial habenula ..................................................................................................................... 10 1.1.1.1 Medial habenula connectivity ............................................................................................. 10 1.1.1.2 Behavioral functions mediated by the medial habenula .................................................... 12 1.1.2 Lateral habenula ..................................................................................................................... 15 1.1.2.1 Lateral habenula connectivity ............................................................................................ 15 1.1.2.2 Behavioral functions mediated by the lateral habenula ..................................................... 16 1.2 G protein-coupled receptors ............................................................................... 18 1.2.1 Classical model of GPCR signaling ........................................................................................ 18 1.2.2 Non-canonical mechanisms of GPCR signaling ..................................................................... 21 1.2.3 Orphan G-protein-coupled receptors ...................................................................................... 22 1.2.3.1 Ligand independent functions or constitutively active orphan receptors ........................... 22 1.3 Gpr151, also known as PGR7, GPCR-2037 or Galanin-receptor like 4 ............. 23 1.4 TRAP analysis of cholinergic MHb neurons reveals enrichment of Gpr151 .... 25 1.5 Aims of this work ................................................................................................. 27 1.5.1 To determine the distribution of the Gpr151 protein in mouse and human brain. .................. 27 1.5.2 To assess the subcellular ultrastructural localization of Gpr151 at habenular axonal terminals in the IPN. ............................................................................................................................... 27 1.5.3 To determine the signaling pathway activated by Gpr151. .................................................... 28 1.5.4 To identify putative ligands of Gpr151. ................................................................................... 28 1.5.5 To elucidate the contribution of Gpr151 to the function of the habenula using genetically modified mice. ......................................................................................................................... 28 2. MATERIALS AND METHODS ..................................................................... 30 2.1 Preface .................................................................................................................. 30 2.1.1 Animals ................................................................................................................................... 30 2.1.2 Chemicals ............................................................................................................................... 30 2.1.3 Buffers and solutions .............................................................................................................. 32 2.1.3.1 General buffers and solutions ............................................................................................ 32 2.1.3.2 Culture media ..................................................................................................................... 33 2.1.3.3 Solutions for behavioral experiments ................................................................................. 33 2.1.4 Molecular biology reagents ..................................................................................................... 33 2.1.4.1 Bacteria strains .................................................................................................................. 33 2.1.4.2 Cell lines ............................................................................................................................. 33 2.1.4.3 Plasmids ............................................................................................................................. 33 2.1.4.4 Primers ............................................................................................................................... 34 2.1.4.5 Oligonucleotides used for shRNA cloning .......................................................................... 34 2.1.4.6 Enzymes............................................................................................................................. 35 2.1.4.7 Kits ..................................................................................................................................... 35 2.1.4.8 Antibodies........................................................................................................................... 35 2.1.4.9 Peptides used for cell-based second messenger assays .................................................. 36 2.1.5 Equipment and software ......................................................................................................... 36 2.1.6 Statistical analyses ................................................................................................................. 38 Contents 6 2.2 Molecular Biology protocols ............................................................................... 38 2.2.1 Vector construction ................................................................................................................
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