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Molecular Mechanisms of Ampa and Kainate Receptor Gating and Its Implication in Synaptic Transmission

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Molecular Mechanisms of Ampa and Kainate Receptor Gating and Its Implication in Synaptic Transmission MOLECULAR MECHANISMS OF AMPA AND KAINATE RECEPTOR GATING AND ITS IMPLICATION IN SYNAPTIC TRANSMISSION Dissertation Zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultäten der Georg-August-Universität zu Göttingen vorgelegt von Naveen Nagarajan aus Mysore, Indien Göttingen, den 17.9.2002 1 D7 Referent: Prof. Dr. Axel Zeeck Korreferent: Prof. Jürgen Troe Tag der mündlichen Prüfung: 2 TABLE OF CONTENTS ABBREVIATIONS.................................................................................................. 8 ABSTRACT ............................................................................................................. 9 1 INTRODUCTION ............................................................................................ 10 1.1 Glutamatergic neurotransmission.............................................................. 10 1.2 Glutamate receptor families...................................................................... 10 1.3 Subunit stoichiometry of AMPA receptors ............................................... 11 1.4 Transmembrane topology and structural implication in ligand binding.................................................................................................... 12 1.5 Gating mechanisms of non-NMDA receptors ........................................... 14 1.5.1 Activation................................................................................... 14 1.5.2 Deactivation and desensitization ................................................. 15 1.6 Modulators of AMPA receptor gating....................................................... 17 1.7 Residues involved in the gating process of AMPA receptor...................... 18 1.8 The role of post transcriptional modifications of AMPA and kainate receptors in gating .................................................................................. 19 1.8.1 RNA editing.............................................................................. 19 1.8.2 Alternative splicing................................................................... 20 1.9 Implication of receptor desensitization and deactivation in synaptic transmission ............................................................................................ 22 2. MATERIAL AND METHODS ........................................................................ 24 2.1 Chemicals and solutions employed........................................................... 24 2.1.1 Electrophysiological studies...................................................... 25 2.1.2 Cell culture ................................................................................ 26 2.2 Preparation of solutions and procedures employed in cell culture and coating ..................................................................................................... 26 2.3 Receptor used in the experiments ............................................................. 27 2.4Mutagenesis methodology........................................................................ 28 2.5 Biochemical analysis................................................................................ 28 2.6 Electrophysiology .................................................................................... 29 2.6.1 The equivalent circuit for a simple cell......................................... 29 2.6.2 An overview of Patch Clamp technique ....................................... 31 2.6.3 Configurations of patch clamp technique ..................................... 33 2.6.4 Experimental procedures.............................................................. 35 2.6.5 Epitope tagging strategy............................................................... 37 2.7 Data analysis ........................................................................................... 38 2.7.1 Software used for the data analysis.............................................. 38 2.7.2 Statistical test for curve fits......................................................... 38 2.7.3 Noise analysis............................................................................. 39 3. RESULTS.......................................................................................................... 40 3.1 Overview................................................................................................ 40 3.2 Gating and assembly properties of AMPA receptors............................... 40 3 3.2.1 Specific gating mechanisms .................................................. 40 3.3 Nondesensitizing phenotype penetrates more readily than desensitzing phenotype.................................................................................................. 43 3.4 Nonrectifying phenotype penetrates more readily than rectifying phenotype.................................................................................................. 44 3.5 Plausible mechanisms for homo and heteromeric AMPA receptor assembly ................................................................................................... 46 3.6 Protein expression is linear to the transfected cDNA concentration............ 47 3.7 Quantification of functional receptor expression........................................ 49 3.8 Quantification of single channel properties of homo and heteromeric AMPA receptors....................................................................................... 50 3.9 Analytical procedures for classification of specific phenotypes in cotransfection experiment.......................................................................... 52 3.9.1 Quantification of desensitizing and nondesensitizing population of receptors ................................................................. 53 3.9.2 No evidence for intermediate desensitization phenotype in cotransfection experiments............................................................. 54 3.9.3 Quantification of rectifying and nonrectifying population of receptors in cotranfection experiments .......................................... 56 3.9.4 No evidence of intermediate phenotype for rectification properties in cotransfection experiments ....................................... 57 3.10 A quantitative model of subunit assembly and phenotype dominance ........ 59 3.10.1 Binomial model for homomeric subunit assembly.......................... 59 3.10.2 Selective assembly model for heteromeric receptors ...................... 61 3.10.3 Model assumptions ........................................................................ 62 3.10.4 Construction of phenotype expression models based on single channel conductance............................................................ 63 3.10.5 Desensitization and Rectification properties in Homo and Heteromeric assembly of AMPA receptors .................................... 65 3.10.5.1 Assembly of homomeric receptors......................................65 3.10.5.2 Assembly of heteromeric receptors.....................................66 3.10.6 More evidences and consistent results in AMPA receptor assembly by altering the markers on different subunits .................. 68 3.10.6.1 Results on homomeric assembly of subunits.................68 3.10.6.2 Results on heteromeric assembly of subunits.................69 3.10.7 Channel properties of AMPA receptor are controlled by spatial arrangement of subunits................................................................... 70 3.10.7.1 Control by desensitization.............................................70 3.10.7.2 Control by rectification.................................................71 3.10.8 Heterodimerization of AMPA receptors............................................ 71 3.10.9 Subunit configuration for heterodimeric assembly of AMPA receptors........................................................................................... 75 3.10.10 Possible mechanisms for subunit assembly of AMPA receptors ................................................................................... 75 3.10.10.1 Symmetry controlled mechanism.................................75 3.10.10.2 Association controlled mechanism...............................77 3.11 Effect of modulators on AMPA receptors................................................. 78 3.11.1 Effect of modulators on recombinant AMPA receptors ................. 78 3.11.1.1 Effect of CX546 on recombinant GluR1 and GluR2 subunits..............................................................................79 4 3.11.1.2 Effect of CX516 and IDRA-21 on recombinant GluR1 and GluR2 receptors..............................................81 3.11.2 Effect of modulators in the absence of desensitization............... 82 3.11.2.1 Effect of CX516 and IDRA 21 on non-desensitizing GluR1receptors...............................................................82 3.11.2.2 Effect of CX546 on nondesensitizing GluR1 receptors........................................................................ 84 3.11.2.3 Additional evidences for the effect of CX546 on gating properties of nondesensitizing GluR1receptors...............................................................85 3.11.3 Specific binding properties of CX546 ....................................... 86 3.11.3.1 Determining the binding properties of CX546 to AMPA receptors................................. ...........................87 3.11.3.1.1 Kinetics of binding in the presence of saturating concentration of glutamate.........87 3.11.3.1.2 Kinetics of binding in the presence of intermediate concentration of glutamate………………………………89
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