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Σ – 1R) Activation and Modulation of Nmda Receptor Surface Expression

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Σ – 1R) Activation and Modulation of Nmda Receptor Surface Expression SIGMA-1 RECEPTOR (σ – 1R) ACTIVATION AND MODULATION OF NMDA RECEPTOR SURFACE EXPRESSION ELITZA HRISTOVA DEPARTMENT OF CELLULAR AND MOLECULAR MEDICINE NEUROSCIENCE PROGRAM UNIVERSITY OF OTTAWA Thesis submitted as partial fulfillments of the requirements for the Master’s Degree in Neuroscience Supervisor Dr. Richard Bergeron © Elitza Hristova, Ottawa, Canada, 2014 i ABSTRACT The sigma-1 receptors (σ-1Rs) are endoplasmic reticulum (ER) resident proteins shown to have chaperone-like functions, and are widely distributed throughout the central nervous system (CNS). They reside at a specialized membrane called mitochondria- associated ER-membrane (MAM) and can modulate numerous voltage- and ligand-gated ion channels. One of these channels is the N-methyl-D-aspartate receptor (NMDAR), and σ-1R ligands are able to enhance the potentiation of NMDARs, but the mechanism involved remains poorly understood. Using various biochemical techniques, we show that 90 min following an i.p. injection of σ-1R agonists ((+)-SKF 10,047 (SKF), (+)- Pentazocine (PTZ), or PRE-084 (PRE), there is an increase in the expression of GluN2- containing NMDARs in the rat hippocampus. These results suggest that σ-1R activation is able to enhance NMDAR function by modulating protein expression levels both in the cytosol and on the cell surface. This suggests that σ-1Rs could be excellent therapeutic targets for many neurological disorders, and for the development of novel antipsychotics. ii TABLE OF CONTENTS ABSTRACT ................................................................................................... ii TABLE OF CONTENTS ............................................................................ iii ACKNOWLEDGEMENTS ........................................................................ vi DEDICATION ........................................................................................... viii LIST OF TABLES ....................................................................................... ix LIST OF FIGURES ...................................................................................... x LIST OF ABBREVIATIONS .................................................................... xii Sigma-1 Receptors (σ-1Rs) ........................................................................... 1 History................................................................................................................................. 1 σ-1R Molecular and Gene Structure ................................................................................... 2 Distribution ......................................................................................................................... 4 System Wide .................................................................................................................... 4 Subcellular ...................................................................................................................... 5 Function .............................................................................................................................. 7 σ-1R Function ................................................................................................................. 7 σ-1R Regulation of Ion Channels .................................................................................... 8 Knockout Model ............................................................................................................... 11 σ-1R Mutations and Involvement in Diseases .................................................................. 12 Mutations ...................................................................................................................... 12 σ-1R Involvement in Diseases ....................................................................................... 14 N-METHYL-D-ASPARTATE RECEPTORS (NMDARs) .................... 17 NMDAR characteristics and Functional Domains ........................................................... 18 NMDAR Genes and Structure .......................................................................................... 20 GluN1 ............................................................................................................................ 20 GluN2 and GluN3 ......................................................................................................... 20 Differences Between Subunits .......................................................................................... 21 NMDAR activation ........................................................................................................... 22 NMDAR Trafficking and Assembly ................................................................................. 23 Trafficking ..................................................................................................................... 23 Assembly ....................................................................................................................... 25 Distribution ....................................................................................................................... 26 Subcellular .................................................................................................................... 26 System Wide .................................................................................................................. 27 iii Function ............................................................................................................................ 28 GluN2A in neuronal survival ........................................................................................ 28 GluN2B in Neuronal Death and Neurodegeneration ................................................... 29 NMDAR Dysfunction/Diseases ........................................................................................ 30 Plasticity ............................................................................................................................ 33 σ-1R Modulation of NMDARs ................................................................... 35 OBJECTIVES ............................................................................................. 38 HYPOTHESIS ............................................................................................ 38 MODEL OF STUDY .................................................................................. 38 METHODS .................................................................................................. 40 Animals ............................................................................................................................. 40 Antibodies ......................................................................................................................... 40 Drugs ................................................................................................................................. 40 Drug administration .......................................................................................................... 41 Isolation of crude synaptosomal fractions ........................................................................ 41 Surface Biotinylation ........................................................................................................ 42 Western blotting and statistical analysis ........................................................................... 43 RESULTS .................................................................................................... 45 σ-1R activation leads to an increase in GluN2-containing NMDARs in the rat hippocampus ..................................................................................................................... 45 No change in AMPAR expression levels following σ-1R agonist administration ........... 47 Upregulation of GluN2-containing NMDARs by σ-1R agonist activation is blocked by σ- 1R antagonists ................................................................................................................... 48 The σ-1R mediated increase in GluN2-containing NMDAR subunit expression is protein synthesis dependent .......................................................................................................... 50 σ-1R activation leads to an increase in surface levels of NMDARs ................................. 51 Increase in surface NMDAR subunit expression is abolished treatment with σ-1R antagonist .......................................................................................................................... 52 DISCUSSION .............................................................................................. 54 CONCLUSION ........................................................................................... 61 TABLES ....................................................................................................... 62 FIGURES ..................................................................................................... 64 REFERENCES ............................................................................................ 75 iv CONTRIBUTIONS OF COLLABORATORS ........................................ 92 v ACKNOWLEDGEMENTS First and foremost, I would like to express my gratitude to Dr. Richard Bergeron for providing me with the opportunity to be a MSc student in his laboratory. Dr. Bergeron delivered me with the platform to acquire indispensible skills in the field of neuroscience and research, but I was also given an
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