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Molecular Mechanisms of Allosteric Modulation of Nicotinic Acetylcholine Receptors

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Molecular Mechanisms of Allosteric Modulation of Nicotinic Acetylcholine Receptors MOLECULAR MECHANISMS OF ALLOSTERIC MODULATION OF NICOTINIC ACETYLCHOLINE RECEPTORS Sean Christopher Barron A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Neurobiology. Chapel Hill 2010 Approved by: Robert L. Rosenberg, Ph.D. (Advisor) Paul B. Manis, Ph.D. (Chair) Jerrel L. Yakel, Ph.D. T. Kendall Harden, Ph.D. Ken D. McCarthy, Ph.D. © 2010 Sean Christopher Barron ALL RIGHTS RESERVED ii ABSTRACT Sean Christopher Barron: Molecular Mechanisms of Allosteric Modulation of Nicotinic Acetylcholine Receptors (under the direction of Dr. Robert L. Rosenberg) Nicotinic acetylcholine receptors (nAChR) are part of the Cys-loop family of ligand-gated ion channels, and are implicated in a wide variety of neurological disorders such as nicotine addiction, schizophrenia, and cognitive dysfunction. Therefore, they represent a critical molecular target for drug development and targeted therapeutic intervention. Positive allosteric modulators (PAMs) of ligand- gated ion channels have a unique therapeutic potential because they enhance synaptic transmission without disrupting the endogenous timing mechanisms. This research focused on the neuronal α7 nicotinic receptor because they are located both pre- and postsynaptically and can modulate glutamatergic and dopaminergic release in the brain regions involved in drug-seeking behaviors. Understanding the molecular mechanisms by which allosteric modulators enhance activation of neuronal nicotinic acetylcholine receptors is therefore critically important to the development of new drugs for research and therapeutics. Experiments with the Substituted Cysteine Accessibility Method indicate that two chemically different positive allosteric modulators, PNU-120596 and permeable divalent cations, cause structural transitions (or changes in local electrostatic potential) in the extracellular ligand binding domain of the α7 nicotinic receptor that iii are similar but not identical to those caused by the agonist, acetylcholine. These results suggest that positive allosteric modulators share a conserved mechanism to enhance receptor gating that is unrelated to the chemical structure of the molecule. As an additional approach to study gating of the nicotinic receptors, I developed homology models derived from the structures of bacterial Cys-loop receptors in the closed and open states. A comparison of electrophysiological MTSEA modification data against in silico calculations of solvent accessibility and electrostatic potential showed that electrostatic potential in the extracellular ligand- binding domain of the α7 nAChR is a better predictor of receptor gating from the closed to open states. Overall, this body of work has shown that positive allosteric modulators and agonists of the α7 nAChR induce similar conformational changes in the extracellular- ligand binding domain of the receptor by reducing the large electronegative potential energy along the ion-permeation pathway. A unifying model of receptor gating (electrostatic compensation) and future experiments designed to test this model are discussed. iv This body of work is dedicated to my wife, Andréa Michelle Barron, for her constant love, support, and patience. To my grandfather, Samuel (Harry) Kasinowitz, who taught me that an education is not fancy titles and degrees but what you choose to do with it. Finally, to my two cats, Garfield and Swee’pea, who have provided company, entertainment, and relaxation while writing my dissertation. v ACKNOWLEDGEMENTS First and foremost, I would like to thank my advisor, Dr. Robert Rosenberg for providing a home to conduct research on ion channels, and a supportive training environment where I could contribute my own ideas. I would like to thank Dr. Jim McLaughlin for being a sounding board for my (sometimes crazy) ideas, and Ms. Jennifer See, Ms. Jie Fu, and Ms. Vanessa Richards for technical support. I would like to thank Dr. Jerry Yakel at NIH/NIEHS for providing support to finish my dissertation, and Mrs. Pattie Lamb and Dr. Anshul Pandya for technical support and training. I would like to thank our collaborator, Dr. Brenda Temple, for teaching me computational modeling from the ground up. I wish to thank Dr. Sharon Milgram of the former IBMS program, for setting me on the path to graduate school. NIDA, NIEHS, the former IBMS program, the Neurobiology Curriculum, and the Department of Pharmacology have contributed to an excellent training environment as well as financial support. I wish to collectively acknowledge the members of my committee, who have taught me to think like a scientist and whose mentorship will impact my career for years to come. Finally, I would like thank the students of the former IBMS program, Department of Pharmacology, and the Neurobiology Curriculum for moral support and humor through this process. vi TABLE OF CONTENTS LIST OF TABLES ...........................................................................................................ix LIST OF FIGURES ..........................................................................................................x LIST OF ABBREVIATIONS .......................................................................................... xii LIST OF ABBREVIATIONS .......................................................................................... xii INTRODUCTION ............................................................................................................ 1 nAChR pharmacology ....................................................................................................... 3 Structural models of nAChRs ......................................................................................... 11 Ion permeation and selectivity of Cys-loop receptors ................................................ 15 Gating of Nicotinic Receptors ......................................................................................... 20 Structural transitions during nAChR gating .................................................................. 24 Positive allosteric modulation ......................................................................................... 29 MATERIALS AND METHODS ..................................................................................... 36 Reagents and Molecular Biology ................................................................................... 37 Two-electrode voltage clamp of Xenopus oocytes ..................................................... 38 Substituted Cysteine Accessibility Method .................................................................. 39 Statistical Analysis ........................................................................................................... 41 Structural models of the α7 nicotinic receptor ............................................................. 41 Homology Modeling and Refinement ............................................................................ 41 Solvent accessibility and continuum electrostatics ..................................................... 43 vii Model Visualization .......................................................................................................... 44 PNU-120596 AND ACETYLCHOLINE CAUSE SIMILAR GATING TRANSITIONS IN THE EXTRACELLULAR LIGAND-BINDING DOMAIN OF THE α7 NICOTINIC RECEPTOR .................................................................................................................. 45 Introduction ........................................................................................................................ 46 Results ............................................................................................................................... 48 Discussion ......................................................................................................................... 68 PERMEABLE DIVALENT CATIONS AND ACETYLCHOLINE CAUSE SIMILAR GATING TRANSITIONS IN THE EXTRACELLULAR LIGAND-BINDING DOMAIN OF THE α7 NICOTINIC RECEPTOR ........................................................................... 77 Introduction ........................................................................................................................ 78 Results ............................................................................................................................... 81 Discussion ......................................................................................................................... 92 HOMOLOGY MODELS OF THE α7 RECEPTOR DERIVED FROM BACTERIAL CYS-LOOP RECEPTORS ............................................................................................ 96 Introduction ........................................................................................................................ 97 Results ............................................................................................................................... 99 Discussion ....................................................................................................................... 118 CONCLUSIONS AND FUTURE DIRECTIONS .......................................................... 129 Agonists and PAMS cause similar conformational changes in the LBD ............... 131 Evidence against the putative Ca 2+ binding site ........................................................ 134 Methodologies to study low-affinity sites ...................................................................
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