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Allosteric Interactions of Gaba- and Glycine-Gated Chloride Channels from Rat Brain

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Allosteric Interactions of Gaba- and Glycine-Gated Chloride Channels from Rat Brain TITLE ALLOSTERIC INTERACTIONS OF GABA- AND GLYCINE-GATED CHLORIDE CHANNELS FROM RAT BRAIN A thesis submitted for the Degree of Doctor of Philosophy, University of London Richard John Prince, BSc August 1992 Department of Pharmacology, School of Pharmacy, University of London, 29-39, Brunswick Square, London WC1N 1AX 1 ProQuest Number: U539242 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest U539242 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 ABSTRACT The allosteric interactions of the GABA a receptor were investigated through the actions of drugs on [H]-flunitrazepam binding. The effects of varying incubation temperature revealed that pentobarbitone is more efficacious a potentiator at low temperatures than at high. In contrast, the general anaesthetics propofol and alphaxalone did not show a variation in efficacy with temperature. These results argue against a membrane site of action for propofol and alphaxalone. Differences in the dependence of potentiation upon anions were also noted. All three drugs gave increased potentiation with increasing concentrations of anions which can permeate the GAB A a receptor. However, whilst the potency of propofol increased with chloride concentration, its efficacy did not Pentobarbitone showed an increase in both potency and efficacy but whilst alphaxalone’s efficacy increased, its potency did not. These results indicate different sites and modes of interaction for propofol, alphaxalone and pentobarbitone. Interactions of the steroid epipregnanolone with the receptor were also characterised. It antagonised competitively the potentiation produced by its isomers pregnanolone and allopregnanolone whilst having little direct effect upon flunitrazepam binding or on potentiation by pentobarbitone and GABA. Epipregnanolone also antagonised the potentiating effect of alphaxalone but the mode of inhibition was different to that seen against pregnanolone, indicating more than one class of binding site for neurosteroids at the GABA a receptor. [3H]-flunitrazepam binding to GABA a receptors immunopurified according to a subunit content was also examined. No potentiation by alphaxalone or pentobarbitone was seen but differences in flunitrazepam affinity and EC50 for potentiation by GABA were noted. In an electrophysiological study, the interaction of steroids with the strychnine-sensitive glycine receptor was examined. Certain corticosteroids were shown to be potent enhancers of the actions of glycine and strychnine at this receptor, but steroids which are active on the GABA a receptor showed no effects. 2 TABLE OF CONTENTS ABSTRACT 2 TABLE OF CONTENTS 3 LIST OF FIGURES 7 LIST OF TABLES 9 CHAPTER 1. GENERAL INTRODUCTION 11 GABA a receptor pharmacology 12 Strychnine sensitive glycine receptor pharmacology 13 Molecular biology of ligand-gated chloride channels 14 Aims and objectives 17 CHAPTER 2. METHODS 20 Electrophysiological studies 21 [3H]-strychnine binding 21 GABA a binding studies 25 Data analysis 30 CHAPTER 3. STEROID ANTAGONISTS AT THE GABA a RECEPTOR 32 5P-pregnan-3p-ol-20-one, a specific antagonist 33 at the steroid site of the GABA a receptor-complex Methods 36 Results 37 Discussion 39 3 Differential antagonism by 3p-hydroxy steroids 43 of alphaxalone and pregnanolone potentiation suggest more than one class of binding site for steroids at GABAa receptors. Methods 47 Results 49 Discussion 57 CHAPTER 4. PROPOFOL POTENTIATES THE BINDING OF 61 [3H]-FLUNITRAZEPAM t o THE GABA a RECEPTOR COMPLEX Methods 65 Results 67 Discussion 76 CHAPTER 5. TEMPERATURE AND ANION DEPENDENCE OF 80 ALLOSTERIC INTERACTIONS AT THE y-AMINOBUTYRIC ACID RECEPTOR Methods 84 Results 86 Discussion 99 4 Chapter 6. STEROID INTERACTIONS AT THE STRYCHNINE 104 SENSITIVE GLYCINE RECEPTOR Electrophysiological studies 105 Methods 107 Results 108 Discussion 117 Binding studies 120 Results 120 Discussion 122 CHAPTER 7. CHARACTERISATION OF IMMUNOPURIFIED 124 GABA a RECEPTORS Allosteric interactions of immunopurified receptors 125 Methods 129 Results 132 Discussion 139 [3H]-muscimol/benzodiazepine binding to 143 immunopurified receptors Methods 143 Results 143 Discussion 146 5 CHAPTER 8. GENERAL DISCUSSION 148 Sites of action 149 Nature of the binding sites 152 One site or many? 154 Endogenous ligands 156 Future perspectives 157 ACKNOWLEDGEMENTS 163 APPENDIX I: STEROID STRUCTURES 164 REFERENCES 165 6 List of Figures and Tables Figure 1.1 Membrane disposition of direct-ligand gated ion channels 2.1 Grease gap apparatus used in electrophysiological experiments 3.1 Competitive antagonism of pregnanolone potentiation of [3H]-flunitrazepam binding by epipregnanolone 3.2 Effect of epipregnanolone on pentobarbitone potentiation of [3H]-flunitrazepam binding 3.3 Concentration effect curves for the potentiation of [3H]-flunitrazepam binding by pregnanolone and epipregnanolone 3.4 Competitive antagonism of allopregnanolone’s potentiation of [3H]-flunitrazepam binding by epipregnanolone 3.5 Effect of epipregnanolone upon alphaxalone potentiation of [3H]-flunitrazepam binding 3.6 Effect of alphaxalone on enhancement of [3H]-flunitrazepam binding by pregnanolone 4.1 Interaction of propofol and NaCl in enhancing [3H]-flunitrazepam binding 4.2 Effect of NaCl on propofol’s EC50 4.3 Propofol enhances the affinity of [3H]-flunitrazepam Figure Page 4.4 Effect of propofol on alphaxalone and pentobarbitone interactions 73 5.1 Van’t Hoff plots for [3H]-flunitrazepam binding ± various drugs 92 5.2 Effect of alphaxalone, propofol and pentobarbitone in the presence 95 and absence of 200mM NaCl on [3H]-flunitrazepam binding 5.3 Effect of NaCl on [3H]-flunitrazepam binding ± various drugs 97 5.4 Potentiation of [3H]-flunitrazepam binding by propofol, 98 pentobarbitone and alphaxalone at various [NaCl]. 6.1 Potentiation of glycine responses by DHC 112 6.2 Interaction of strychnine and DHC on responses to glycine 114 6.3 Fade of glycine responses induced by hydrocortisone 116 6.4 Action of DHC on [3H]-strychnine binding 121 7.1 Potentiation by GABA of [3H]-flunitrazepam binding to membranes 134 and immunopurified receptors 7.2 Effect of pentobarbitone and alphaxalone on [3H]-flunitrazepam 135 binding to membranes and immunopurified receptors 7.3 Chloride dependency of [3H]-flunitrazepam 136 binding to membranes and immunopurified receptors 8.1 Model for the interaction of lipids with ligand-gated ion channels 159 8.2 Major pathways for pregnanolone production in the brain 161 8 Table Page 3.1 Parameters for the potentiation of [3H]-flunitrazepam binding 51 by pregnanolone and allopregnanolone under various conditions 3.2 Effect of 36-OH steroids on the potentiation of [3H]-flunitrazepam 52 binding by alphaxalone and 56-alphaxalone 4.1 Effect of various salts on the EC50 of propofol for the potentiation 74 of [3H]-flunitrazepam binding 4.2 Effect of propofol upon concentration effect parameters for the 75 potentiation of [3H]-flunitrazepam by alphaxalone and pentobarbitone 5.1 Thermodynamic parameters for [3H]-flunitrazepam binding in the 89 presence of propofol, alphaxalone and pentobarbitone 5.2 EC50s of propofol, alphaxalone and pentobarbitone at 4 and 37°C 90 for the potentiation of [3H]-flunitrazepam binding 5.3 EC50s of propofol, alphaxalone and pentobarbitone in the presence 91 of various salts 6.1 Log shifts of the dose response curve to glycine 111 7.1 EC50s for GABA, pentobarbitone and alphaxalone enhancement of 137 [3H]-flunitrazepam binding to native and immunopurified receptors 7.2 Affinity of [3H]-flunitrazepam in native and immunopurified 138 receptors at 4 and 37°C ± lOOpM GABA 9 Table Page 7.3 Kd values for muscimol, R015 1788 and flunitrazepam in 144 immunopurified receptors 7.4 Benzodiazepine/muscimol binding ratios in immunopurified receptors 145 10 CHAPTER 1 General Introduction 11 Chapter 1: General Introduction GENERAL INTRODUCTION Fast synaptic inhibition in the central nervous system is largely mediated by chloride ion channels gated by the inhibitory amino acids glycine and GABA (Y-aminobutyric acid). In the higher areas of the CNS, GABA is the dominant inhibitory transmitter whilst in the spinal cord this function is fulfilled by glycine. Up-regulation of these systems results in an increase in synaptic inhibition which manifests itself in sedation, anaesthesia and muscle relaxation, whilst a decrease in inhibitory function causes hyperexcitability resulting in convulsions, and epileptiform activity. Alterations in inhibitory function are both implicated in disease and exploited in therapeutic strategy (Martin, 1987; Lloyd et al, 1984; Faingold and Browning, 1987; Buckle et al> 1989). Many of the best known and most widely-prescribed hypnotic drugs act at the GAB Aa receptor. Pharmacology of theGABA a receptor In addition to gating by the neurotransmitter GABA, the GABA a receptor is modulated by a wide range of drugs acting at distinct loci (for reviews see Tallman and Gallager, 1985; Stephenson, 1988; Schwartz, 1988). These substances allosterically modulate both the GABA binding
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