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Allosteric Modulation of Metabotropic Glutamate Receptors

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Allosteric Modulation of Metabotropic Glutamate Receptors ALLOSTERIC MODULATION OF METABOTROPIC GLUTAMATE RECEPTORS By Shen Yin 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 December, 2013 Nashville, Tennessee Approved: Vsevolod V. Gurevich, Ph.D. Richard M. Breyer, Ph.D. Roger J. Colbran, Ph.D. Danny G. Winder, Ph.D. P. Jeffrey Conn, Ph.D. Colleen M. Niswender, Ph.D. ACKNOWLEGEMENTS I would like to express my deep appreciation and gratitude to my advisor, Dr. Jeff Conn and Dr. Colleen Niswender, for having me take part in their research and for the patient guidance and mentorship that they have granted me. Together, they have helped me with every aspect of my Ph.D training and provided me with invaluable opportunities to explore the beauty of science. I would be proud to keep everything they have given me in heart and carry it on to my future career. I would also like to thank my committee members, Dr. Vsevolod Gurevich, Dr. Roger Colbran, Dr. Danny Winder and Dr. Richard Breyer, four distinguished scientists for their thought-provoking suggestions both for my thesis research and for my career development. They have always been encouraging, inspiring and ready to help all the way along my Ph.D study. Hereby, I would like to express my sincere thank you to each of my committee members. I will not be able to accomplish my study without the help of all the past and present members of Conn Lab and other labs at Vanderbilt Center for Neuroscience Discovery. As a more senior graduate student in the Conn Lab, Dr. Kari Johnson has shared her precious experience with me at each step of my Ph.D training. I want to thank her for her generosity and wish her all the best on her future career. Throughout my four years in the Conn Lab, Rocio Zamorano has always been a great teacher when I learn new techniques, ii a helpful colleague to achieve success together and a good friend of mine to share the exciting moments. Drs. Meredith Noetzel, Kari Johnson, Nidhi Jalan-Sakrikar and Karen Gregory have kindly collaborated with me on my thesis project and have significantly contributed to the work. Dr. Douglas Sheffler and Dr. Hyekyung Cho Plumley have nicely trained me for experimental design and procedures and shared with me a number of experimental protocols. And all the rest of Conn Lab members have created a friendly, stimulating and enjoyable environment for me to work in and contributed to my work on some level. In addition, the work presented in this dissertation would not have been possible without several funding sources. I deeply appreciate grants from the National Institutes of and the Vanderbilt International Scholar Program. Finally, I would give my deepest appreciation to my parents and my boyfriend Jiang, who have always devoted themselves to share the happiness and support me in difficult situations. I also want to thank my dear friends in the Department of Pharmacology: Dr. Jing Jin, Craig Goodwin, Tu Mai, Jing Wu and many others, who have made my life at Vanderbilt so memorable. iii TABLE OF CONTENTS Page ACKNOWLEDGMENTS .................................................................................................. ii LIST OF TABLES ............................................................................................................ vii LIST OF FIGURES ......................................................................................................... viii LIST OF ABBREVIATIONS ............................................................................................ xi Chapter I. GENERAL INTRODUCTION ............................................................................... 1 Metabotropic glutamate receptors .......................................................................... 1 Classification of mGlus .............................................................................. 1 Structure of mGlus ..................................................................................... 5 Signaling of mGlus .................................................................................... 9 Allosteric modulation of mGlu ............................................................................ 15 Therapeutic indications of mGlu4 ............................................................ 15 Mechanism of allosteric modulation ........................................................ 17 Allosteric modulators for mGlu2 and mGlu4 ........................................... 20 Advantages and complications of allosteric modulation ......................... 22 II. FUNCTIONAL SELECTIVITY INDUCED BY MGLU4 RECEPTOR ALLOSTERIC MODULATORS DURING CONCOMITANT ACTIVATION OF Gq COUPLED RECEPTORS .................................................... 24 Introduction ........................................................................................................... 24 iv Methods ................................................................................................................. 27 Results .................................................................................................................. 33 Activation of histamine H1 receptor biases the signaling of mGlu4 toward calcium mobilization .................................................................... 33 Concomitant activation of Gq coupled receptors pathway-selectively potentiate the calcium signaling of Gi-coupled receptors ........................ 41 Functionally selective effects of mGlu4 positive allosteric modulators induced by co-activation of H1 and mGlu4 .............................................. 42 Exploration of H1-mGlu4 signaling crosstalk in native tissues ................. 50 Discussion ............................................................................................................ 51 III. HETERODIMERISATION OF MGLU2/4 DIFFERENTIALLY REGULATE EFFECT OF ALLOSTERIC MODULATORS ............................ 56 Introduction ........................................................................................................... 56 Methods ................................................................................................................. 58 Results ................................................................................................................... 72 mGlu4 interacts with mGlu2 to form heterocomplexes both in vitro and in brain tissue ..................................................................................... 72 mGlu2/4 heteromer differentially regulate the effect of mGlu4 allosteric modulators ................................................................................. 78 Co-addition of mGlu2 PAM and mGlu4 PAM does not result in further potentiation .................................................................................... 96 Allosteric modulators of mGlu2 are also differentially regulated upon formation of mGlu2/4 heteromer ..................................................... 101 v mGlu2 and 4 allosteric modulators exhibit unique pharmacological effect at the corticostriatal synapse ......................................................... 108 Discussion ........................................................................................................... 113 IV. GENERAL DISCUSSION AND FUTURE DIRECTIONS .............................. 118 Functional selectivity and therapeutic implications of mGlu allosteric modulators ............................................................................ 118 Receptor assembly-selective modulators of mGlu ............................................ 123 mGlu2/4 heteromer as a biomarker for Parkinson’s Disease .............................. 127 BIBLIOGRAPHY ........................................................................................................... 130 vi LIST OF TABLES Table Page 1.1. Classification, G protein coupling, splice varients and selective ligands for mGlu subtypes ............................................................... 3 3.1. Potencies and efficacies of orthosteric agonists in various cell lines ................... 85 3.2. The ability of mGlu4 PAMs to left-shift agonist concentration-response curves is distinct for different groups of PAMs ............................................................. 92 3.3. Analysis of mGlu4 PAMs using the operational model of allosterism reveals differential alterations in affinity or cooperativity for distinct groups of PAMs ................................................................................................... 97 3.4. Differential leftward fold shifts of glutamate or L-AP4 concentration -response curves are induced by different PAMs after transient expression of increasing amounts of mGlu2 (0, 0.1, 0.2, 0.5 or 1 µg) with a constant amount (1 µg) of mGlu4 ............................................................................ 98 3.5. The efficacy of mGlu2 PAMs to left-shift agonist concentration-response curves differs between classes of PAMs ............................................................ 104 3.6. MNI-137 exhibits enhanced affinity but decreased efficacy in modulating DCV-IV responses in mGlu2/4 cells compared to cells expressing mGlu2 alone .................................................................................................................... 109 vii LIST OF FIGURES Figure Page 1.1. Signaling pathways of mGlu receptors ................................................................ 10 1.2. Mechanism of action of
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