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Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A

Nature Neuroscience volume 4, pages 894–901 (2001)Cite this article

Abstract

Fast desensitization is an important regulatory mechanism of neuronal NMDA receptor function. Only recombinant NMDA receptors composed of NR1/NR2A exhibit a fast component of desensitization similar to neuronal NMDA receptors. Here we report that the fast desensitization of NR1/NR2A receptors is caused by ambient zinc, and that a positive allosteric interaction occurs between the extracellular zinc-binding site located in the amino terminal domain and the glutamate-binding domain of NR2A. The relaxation of macroscopic currents reflects a shift to a new equilibrium due to increased zinc affinity after binding of glutamate. We also show a similar interaction between the ifenprodil binding site and the glutamate binding site of NR1/NR2B receptors. These data raise the possibility that there is an allosteric interaction between the amino terminal domain and the ligand-binding domain of other glutamate receptors. Our findings may provide insight into how zinc and other extracellular modulators regulate NMDA receptor function.

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Figure 1: Desensitization of recombinant NR1/NR2A receptors has two kinetic components.
Figure 2: EDTA abolishes the fast component of NR1/NR2A receptor desensitization.
Figure 3: Tricine-buffered zinc causes fast desensitization of recombinant and neuronal NR1/NR2A receptors.
Figure 4: Histidine point mutations in the amino terminal domain of NR2A abolish the fast desensitization of NR1/NR2A receptors.
Figure 5: The degree and the time course of the zinc-induced fast desensitization of NR1/NR2A receptors depend on extracellular free zinc concentration.
Figure 6: pH influences zinc-induced fast desensitization of NR1/NR2A receptors.
Figure 7: Ifenprodil produces desensitization of NR1/NR2B receptors.
Figure 8: A model for an allosteric interaction between the amino terminal domain and S1/S2 domain of NR2.

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Acknowledgements

We thank M.L. Mayer, J. Neyton and P. Paoletti for reading the manuscript. S. F. Heinemann provided NR1 and NR2B. S. Nakanishi provided NR2A. D. Lynch and E. Aizenman provided NR2B(E201R). This work is supported by grants from NINDS (NS 39418 to F.Z., NS 36654 to S.F.T. and NS 31373 and NS 34876 to P.J. Conn), HHMI (K.E.), the Benzon Society (T.B.) and a Young Investigator Award from NARSAD to F.Z.

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Author notes

  1. C.-M. Low

    Present address: National Neuroscience Institute, 11 Jalan Tan Tock Seng, S308433, Singapore

  2. P. J. Conn

    Present address: Merck Research Laboratories, 770 Sumneytown Pike, PO Box 4, WP46-300, West Point, Pennsylvania, 19486-0004, USA

Authors and Affiliations

  1. Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, 30322, Georgia, USA

    F. Zheng, K. Erreger, C.-M. Low, T. Banke, C. J. Lee, P. J. Conn & S. F. Traynelis

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Correspondence to F. Zheng.

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Zheng, F., Erreger, K., Low, CM. et al. Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A. Nat Neurosci 4, 894–901 (2001). https://doi.org/10.1038/nn0901-894

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