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Williams Dissertation 4.17.12 ACTIVATION, DESENSITIZATION AND POTENTIATION OF ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTORS: RELEVANCE TO ALPHA7-TARGETED THERAPEUTICS By DUSTIN KYLE WILLIAMS A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2012 1 © 2012 Dustin Kyle Williams 2 To the most important people in my life: my family 3 ACKNOWLEDGMENTS I would like to thank my wife, Julie Williams, and my parents, Kevin and Kathy Williams for their unconditional love and flawless support through the graduate school experience, even when I have had to place work before them. I would like to thank Dr. Roger Papke for his mentorship over the last five years. I have had more success under his arm than I ever could have expected when I started graduate school. In addition, I am thankful for the many collaborative meetings I participated in with Dr. Nicole Horenstein and Dr. Jingyi Wang. I would like to thank Mathew Kimbrell for his fine work in helping to create the stably transfected cell lines, and for the interactions I have had with all members of the Papke laboratory. I wish to express gratitude to the members of my advisory committee, Dr. Nicole Horenstein, Dr. Brian Cooper, Dr. Michael King, and Dr. Brian Law, for their counsel and guidance. I am thankful for the financial support I have received from the National Institute on Aging Training Grant T32-AG000196. 4 TABLE OF CONTENTS Page ACKNOWLEDGMENTS ................................................................................................... 4 LIST OF TABLES ............................................................................................................. 8 LIST OF FIGURES ........................................................................................................... 9 LIST OF ABBREVIATIONS ............................................................................................ 12 ABSTRACT .................................................................................................................... 14 CHAPTER 1 ANIMAL ELECTRICITY: HISTORICAL INTRODUCTION ..................................... 16 Pre-Galvani to Hodgkin & Huxley ............................................................................ 16 Chemical Neurotransmission, Receptors, and Ion Channels .................................. 28 2 NICOTINIC ACETYLCHOLINE RECEPTORS: INTRODUCTION ......................... 37 The Cys-Loop Superfamily of Ligand-Gated Ion Channels .................................... 37 nAChRs of muscle and electric organs .................................................................. 38 General Features of nAChR Structure Learned from Muscle-type nAChRs .......... 38 Neuronal nAChR Subunits ..................................................................................... 41 Physiology, Expression, and Functional Roles of Muscle-type nAChRs ................ 43 Physiology, Expression, and Functional Roles of Neuronal nAChRs ..................... 44 General Distinguishing Features of Neuronal nAChRs ..................................... 44 Peripheral Neuronal nAChRs ............................................................................ 45 Central Neuronal nAChRs ................................................................................ 45 High-Affinity Binding Sites ................................................................................. 49 Low-Affinity Binding Sites: α7 nAChRs ................................................................. 51 Distinguishing Functional Characteristics of the homomeric α7 nAChR ........... 51 Implications of α7 nAChR in Pathophysiology .................................................. 54 Therapeutic Targeting of the α7 nAChR through Positive Allosteric Modulation ......................................................................................................... 57 3 METHODS .............................................................................................................. 65 !!!!cDNA Clones ........................................................................................................... 65 Chemicals ................................................................................................................ 65 Site-Directed Mutations ........................................................................................... 66 Preparation of RNA for Injections into Xenopus laevis Oocytes .............................. 66 Expression in Xenopus laevis Oocytes ................................................................... 66 Two-Electrode Voltage Clamp Electrophysiology .................................................... 67 Transient Transfection of BOSC23 Cells ................................................................. 69 Generation of HEK293 Cells Stably Expressing Human α7 and Human ric3 ......... 70 Immunoprecipitation and Western Blot .................................................................... 72 Fluorescence Microscopy ........................................................................................ 73 Equillibrium Radioligand Binding Assay .................................................................. 73 Cytotoxicity Experiments ......................................................................................... 74 5 Outside-out Patch Clamp Electrophysiology ........................................................... 75 !!!!Whole-cell Patch Clamp Electrophysiology ............................................................. 79 4 DIFFERENTIAL REGULATION OF RECEPTOR ACTIVATION AND AGONIST SELECTIVITY BY HIGHLY CONSERVED TRYPTOPHANS IN THE NICOTINIC ACETYLCHOLINE RECEPTOR BINDING SITE .................................................... 83 Introduction ............................................................................................................. 83 Results .................................................................................................................... 85 Mutation of W55 or W57 of α7 and α4β2 Receptors, respectively, Alters the Pharmacology and Regulates the Selectivity of 4OH-GTS-21. ......................... 85 Absolute Efficacy of ACh ................................................................................... 86 Relative Efficacy of α7 selective Agonists Compared with ACh ........................ 87 Mutation of W149 in Both α7 and α4β2 Receptors Reduced Receptor Activation by Both ACh and α7 Selective Agonists. ........................................................... 90 Discussion ............................................................................................................... 91 5 THE EFFECTIVE OPENING OF NICOTINIC ACETYLCHOLINE RECEPTORS WITH SINGLE AGONIST BINDING SITES .......................................................... 104 Introduction ........................................................................................................... 104 Results .................................................................................................................. 105 Identification of the α7L119C Mutation as a Tool to Study nAChR Binding Sites ................................................................................................................. 106 Effects of α7L119C Ratios in Mixed α7 Wild Type/Mutant Heteromers ........... 106 Effects of ACh-Insensitive Mutant Ratios in Mixed α7 Wild Type/Mutant Heteromers ...................................................................................................... 108 Effects of Mutations Homologous to α7L119C in Non-α Subunits of Muscle- Type Receptors ................................................................................................ 109 Discussion ............................................................................................................. 115 6 INVESTIGATION OF THE MOLECULAR MECHANISM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR POSITIVE ALLOSTERIC MODULATOR PNU-120596 PROVIDES EVIDENCE FOR TWO DISTINCT DESENSITIZED STATES ................................................................................... 130 Introduction ........................................................................................................... 130 Results ................................................................................................................... 131 ACh-Evoked Responses of α7 nAChR Expressed in Xenopus Oocytes ......... 131 ACh-Evoked Responses of α7 nAChR Expressed in BOSC23 Cells in the Absence and Presence of PNU-120596 .......................................................... 132 Factors Limiting the Potentiating Effects of PNU-120596 on α7-Mediated Currents ........................................................................................................... 134 Single-Channel Bursts of α7 nAChR Promoted by PNU-120596 .................... 136 Discussion ............................................................................................................. 141 6 7 A NOVEL CELL LINE STABLY EXPRESSING HUMAN ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTORS REVEALS THAT PNU-120596 POTENTIATION AND CYTOTOXICITY ARE ATTENUATED AT PHYSIOLOGICAL TEMPERATURE ................................................................................................... 155 Introduction ............................................................................................................ 155 Results ..................................................................................................................
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