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Author Notes:

Dr. Hiro Furukawa, Cold Spring Harbor Laboratory, Keck Structural Biology Laboratory, 1 Bungtown Rd., Cold Spring Harbor, NY, 11724, USA. Tel: 516-316-8872; Fax: 516-316-8873; furukawa@cshl.edu.

K.M.V. performed electrophysiology experiments; N.S. and H.F. conducted X-ray crystallographic studies; K.M.V., S.T. and H.F. designed the experiments and wrote the paper.

We thank Erkan Karakas for help in collection of x-ray diffraction data, and Kasper Hansen and Hongjie Yuan for critical comments on the manuscript.

We also thank Alasdair Gibb for advice on kinetic modeling and critical comments on the manuscript.

We also thank the staffs at beamlines X25, X26C, and X29 of the National Synchrotron Light Source.

The authors declare no competing financial interests.

Subjects:

Research Funding:

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).

HF is also supported by a new investigator research grant from Alzheimer’s Association.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • D-ASPARTATE RECEPTORS
  • GLUTAMATE RECEPTORS
  • CRYSTAL-STRUCTURES
  • HOMOCYSTEIC ACID
  • BINDING CORE
  • SYNAPTIC CURRENTS
  • FALSE TRANSMITTER
  • CHANNEL KINETICS
  • CENTRAL NEURONS
  • PARTIAL AGONISM

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

Tools:

Journal Title:

Nature Communications

Volume:

Volume 2, Number 1

Publisher:

, Pages 294-294

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2011 Macmillan Publishers Limited. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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