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Slow Mg Unblock and Inherent Voltage Dependence of NMDA Receptors By Slow Mg2+ unblock and inherent voltage dependence of NMDA receptors by Richard J. Clarke Bachelor of Science, Allegheny College, 2000 Submitted to the Graduate Faculty of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2006 UNIVERSITY OF PITTSBURGH School of Arts and Sciences This dissertation was presented by Richard J. Clarke It was defended on July 17, 2006 and approved by Elias Aizenman, Ph.D. Germán Barrionuevo, M.D. Peter Drain, Ph.D. Stephen Traynelis, Ph.D. Nathan Urban, Ph.D. Dissertation Advisor: Jon Johnson, Ph.D. ii Copyright © by Richard J. Clarke 2006 iii Slow Mg2+ unblock and inherent voltage dependence of NMDA receptors Richard J. Clarke, PhD University of Pittsburgh, 2006 N-methyl-D-aspartate (NMDA) receptors are a subtype of ligand-gated ionotropic glutamate receptors that are involved in most fast, excitatory neuronal transmission in the mammalian central nervous system (CNS). NMDA receptor activity is crucial for normal brain function, and NMDA receptor dysregulation has been linked to a number of diseases of the CNS. There are several NMDA receptor subtypes. Each subtype has a unique temporal and spatial expression pattern, suggesting that different subtypes play different physiological roles in the CNS. Here, we have investigated how changes in membrane voltage impact the activity of various NMDA receptor subtypes in the absence and presence of the highly physiologically relevant channel blocker magnesium (Mg2+). Mg2+ strongly blocks all NMDA receptor subtypes at, and near, typical resting membrane potentials. Only upon depolarization is Mg2+ block relieved. We found that, upon depolarization, NMDA receptors containing NR2C or NR2D subunits unblock Mg2+ very rapidly (τ < 1 ms), while Mg2+ unblock from NMDA receptors containing the NR2A or NR2B subunit displays a prominent slow component (τ of several ms). We go on to show that the slow component of Mg2+ unblock from NR2A and NR2B containing NMDA receptors actually reflects inherent voltage-dependent alterations in NMDA receptor gating. In the absence of Mg2+, NR2A and NR2B containing NMDA receptor currents are enhanced upon membrane depolarization. Utilizing data collected in the absence of Mg2+, we developed kinetic models of NR2A and NR2B containing NMDA receptors that included inherent voltage sensitivity such that the receptors open more rapidly at positive membrane potentials. The NR2 subunit specific models reproduce experimentally recorded currents during changes in membrane voltage in both the absence and presence of Mg2+. The models also reproduce several other previously described voltage-dependent characteristics of the NMDA receptor channel. Inherent voltage dependence further emphasizes the strong link between NMDA receptor activity and neuronal depolarization. iv TABLE OF CONTENTS PREFACE.................................................................................................................................XIII 1.0 INTRODUCTION........................................................................................................ 1 1.1 GLUTAMATE RECEPTOR SUBTYPE DIVERSITY ................................... 2 1.1.1 Subunit identification and genetic diversity............................................... 4 1.1.2 Subunit-dependent receptor properties...................................................... 4 1.1.3 Regulation of subunit expression................................................................. 5 1.1.4 Triheteromeric receptors ............................................................................. 6 1.2 NMDA RECEPTOR STRUCTURE.................................................................. 7 1.2.1 Membrane topology...................................................................................... 7 1.2.2 Extracellular domains .................................................................................. 7 1.2.3 Transmembrane segments and ion permeation......................................... 8 1.2.4 Location of the activation gate................................................................... 10 1.2.5 Intracellular segment.................................................................................. 11 1.3 RECEPTOR ACTIVATION ............................................................................ 12 1.3.1 Activation and deactivation of NMDA receptors..................................... 12 1.3.2 NMDA receptor desensitization................................................................. 12 1.3.3 Modeling receptor activation..................................................................... 13 1.3.4 NMDA receptor gating models.................................................................. 14 1.4 VOLTAGE-DEPENDENT MODULATION OF LIGAND-GATED RECEPTORS...................................................................................................................... 16 1.4.1 Membrane voltage and glutamate receptor activity................................ 16 1.5 MAGNESIUM BLOCK AND UNBLOCK OF NMDA RECEPTORS........ 17 2+ 1.5.1 NR2 subunit differences in Mg o block.................................................... 18 2+ 1.5.2 Kinetics of Mg o unblock .......................................................................... 18 v 1.6 CHANNEL BLOCK AND NMDA RECEPTOR GATING .......................... 19 1.6.1 Interaction between blockers and gating machinery............................... 19 2+ 1.6.2 Mg o block and NMDA receptor gating .................................................. 20 1.7 GOALS OF THIS DISSERTATION............................................................... 21 1.7.1 NMDA receptor NR2 subunit dependence of the slow component of 2+ Mg o unblock............................................................................................................. 21 1.7.2 Modulation of NR1/2B receptor activation by membrane voltage. ....... 22 1.7.3 Voltage-dependent modulation of NMDA receptor activation: NR2 2+ subunit dependence and slow Mg o unblock. ......................................................... 22 2.0 NMDA RECEPTOR NR2 SUBUNIT DEPENDENCE OF THE SLOW COMPONENT OF MAGNESIUM UNBLOCK...................................................................... 23 2.1 ABSTRACT........................................................................................................ 23 2.2 INTRODUCTION ............................................................................................. 24 2.3 MATERIALS AND METHODS...................................................................... 25 2.3.1 Cell culture and transfection...................................................................... 25 2.3.2 Solutions....................................................................................................... 26 2.3.3 Whole-cell recording................................................................................... 26 2.3.4 Data analysis and Curve Fitting ................................................................ 27 2.4 RESULTS ........................................................................................................... 28 2+ 2.4.1 NR2 subunit identity controls Mg o unblocking kinetics....................... 28 2+ 2.4.2 Voltage Dependence of Slow Mg o Unblock ............................................ 33 2+ 2.4.3 Dependence of Mg o unblocking kinetics on agonist concentration ..... 39 2+ 2.4.4 Effect of the timing of membrane depolarization on Mg o unblocking kinetics ...................................................................................................................... 42 2+ 2.4.5 Effect of varying the duration of depolarization on Mg o unblock....... 45 2.5 DISCUSSION..................................................................................................... 49 2.5.1 Comparison with previous studies ............................................................ 49 2.5.2 Implications for synaptic plasticity ........................................................... 51 3.0 MODULATION OF NR1/2B RECEPTOR ACTIVATION BY MEMBRANE VOLTAGE................................................................................................................................... 54 3.1 ABSTRACT........................................................................................................ 54 vi 3.2 INTRODUCTION ............................................................................................. 54 3.3 MATERIALS AND METHODS...................................................................... 56 3.3.1 Cell culture and transfection...................................................................... 56 3.3.2 Solutions....................................................................................................... 56 3.3.3 Whole-cell recording................................................................................... 57 3.3.4 Data analysis and Curve Fitting ................................................................ 57 3.3.5 Kinetic Modeling......................................................................................... 57 3.4 RESULTS ........................................................................................................... 58 3.4.1 Slow development of outward currents persists in the absence of 2+ Mg o ...................................................................................................................... 58 3.4.2 Inherent voltage dependence of NR2 subunit gating..............................
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