Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors

• Type of Material: Article
• Authors: Katie M. Vance, Emory University; Noriko Simorowski, Cold Spring Harbor Laboratory; Stephen Traynelis, Emory University; Hiro Furukawa, Cold Spring Harbor Laboratory
• Language: English
• Date: 2011-04-01
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2011 Macmillan Publishers Limited. All rights reserved.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms1295
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 2
• Issue: 1
• Start Page: 294
• End Page: 294
• Grant/Funding Information: HF is also supported by a new investigator research grant from Alzheimer’s Association.; This work was supported by the NINDS (NS036654, NS065371 to SFT); NIH training grants (T32-ES012870 and T32-DA01504006, KMV); NIMH (MH085926-01A1 to HF).
• Keywords: Science & Technology - Other Topics; GLUTAMATE RECEPTORS; FALSE TRANSMITTER; PARTIAL AGONISM; CENTRAL NEURONS; SYNAPTIC CURRENTS; HOMOCYSTEIC ACID; D-ASPARTATE RECEPTORS; BINDING CORE; CRYSTAL-STRUCTURES; CHANNEL KINETICS; Multidisciplinary Sciences; Science & Technology
• Research Categories: Biology, Physiology; Health Sciences, Pharmacology

Abstract

N-methyl-D-aspartate (NMDA) receptors belong to the family of ionotropic glutamate receptors that mediate a majority of excitatory synaptic transmission. One unique property of GluN1/GluN2D NMDA receptors is an unusually prolonged deactivation time course following the removal of L-glutamate. Here we show, using x-ray crystallography and electrophysiology, that the deactivation time course of GluN1/GluN2D receptors is influenced by the conformational variability of the ligand-binding domain (LBD) as well as the structure of the activating ligand. L-glutamate and L-CCG-IV induce significantly slower deactivation time courses compared with other agonists. Crystal structures of the isolated GluN2D LBD in complex with various ligands reveal that the binding of L-glutamate induces a unique conformation at the backside of the ligand-binding site in proximity to the region at which the transmembrane domain would be located in the intact receptors. These data suggest that the activity of the GluN1/GluN2D NMDA receptor is controlled distinctively by the endogenous neurotransmitter L-glutamate.