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Subunit arrangement and function in NMDA receptors

Nature volume 438, pages 185–192 (2005)Cite this article

Abstract

Excitatory neurotransmission mediated by NMDA (N-methyl-d-aspartate) receptors is fundamental to the physiology of the mammalian central nervous system. These receptors are heteromeric ion channels that for activation require binding of glycine and glutamate to the NR1 and NR2 subunits, respectively. NMDA receptor function is characterized by slow channel opening and deactivation, and the resulting influx of cations initiates signal transduction cascades that are crucial to higher functions including learning and memory. Here we report crystal structures of the ligand-binding core of NR2A with glutamate and that of the NR1–NR2A heterodimer with glutamate and glycine. The NR2A–glutamate complex defines the determinants of glutamate and NMDA recognition, and the NR1–NR2A heterodimer suggests a mechanism for ligand-induced ion channel opening. Analysis of the heterodimer interface, together with biochemical and electrophysiological experiments, confirms that the NR1–NR2A heterodimer is the functional unit in tetrameric NMDA receptors and that tyrosine 535 of NR1, located in the subunit interface, modulates the rate of ion channel deactivation.

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Figure 1: Oligomeric arrangement in NMDA receptors.
Figure 2: Structure of NR1–NR2A S1S2.
Figure 3: Engineering disulphide bonds at the NR1–NR2A heterodimer interface.
Figure 4: Heterodimerization is favoured in NR1 S1S2 N521Y and NR2A S1S2 E516Y.
Figure 5: Superposition of NR1–NR2A S1S2 and the GluR2 S1S2–aniracetam complex.
Figure 6: Residue NR1 Y535 modulates the rate of NMDA receptor deactivation.

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Acknowledgements

We are grateful to A. Rowe for comments on the sedimentation equilibrium data analysis. M. Mayer is thanked for discussions, critical reading of this manuscript, and pSP NR1-1a and NR2A. J. Howe and S. Traynelis are thanked for comments on electrophysiological experiments and for the TsA201 cell-line and pCINEO NR1-1a and NR2A, respectively. We thank N. Armstrong, W. Zhang, and A. Robert for instructions on the patch-clamp and rapid solution exchange experiments; R. Abramowitz and X. Yang for assistance with the X-ray experiments; S. Siegelbaum for providing Xenopus oocytes; and A. Sobolevsky and O. Boudker for critically reading the manuscript. The NR1 and NR2A cDNAs used in the structural analysis were a gift from S. F. Heinemann. S.K.S is supported by an NIH National Research Service Award postdoctoral fellowship. The Beckman XL-I analytical centrifuge was purchased with funds from the NIH. The work was supported by the NIH. E.G. is an investigator with the Howard Hughes Medical Institute.

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Author notes

  1. Hiroyasu Furukawa, Satinder K Singh & Eric Gouaux

    Present address: Vollum Institute, Oregon Health and Science University, Portland, Oregon, 97239, USA

  2. Romina Mancusso

    Present address: The Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, USA

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biophysics,

    Hiroyasu Furukawa, Satinder K Singh, Romina Mancusso & Eric Gouaux

  2. Howard Hughes Medical Institute, Columbia University, 650 West 168th Street, New York, 10032, New York, USA

    Romina Mancusso & Eric Gouaux

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Correspondence to Eric Gouaux.

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The coordinates and structure factors for NR1–NR2A S1S2 and NR2A S1S2–glutamate have been deposited in the Protein Data Bank with accession codes 2A5T and 2A5S, respectively. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

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This file contains Supplementary Methods, Supplementary Figure Legends, Supplementary Tables 1–4 and Supplementary Figures 1–4. (PDF 2344 kb)

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Furukawa, H., Singh, S., Mancusso, R. et al. Subunit arrangement and function in NMDA receptors. Nature 438, 185–192 (2005). https://doi.org/10.1038/nature04089

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