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Activation of NR1/NR2B NMDA receptors

Nature Neuroscience volume 6, pages 144–152 (2003)Cite this article

Abstract

N-methyl-D-aspartate (NMDA) receptors are highly expressed in the central nervous system and are involved in excitatory synaptic transmission as well as synaptic plasticity. Despite considerable structural and biophysical research, the mechanism behind activation of the NMDA receptor is still poorly understood. By analyzing patch clamp recordings of one channel activated by glutamate, we determined the burst structure and open probability for recombinant rat NR1/NR2B receptors. We used partial agonists at the glutamate and glycine binding sites to show that at least two kinetically distinct subunit-associated conformational changes link co-agonist binding to the opening of the NMDA receptor pore. These data suggest that NR1 and NR2B subunits, respectively, undergo a fast and slow agonist-dependent conformational change that precedes opening of the pore. We propose a new working model of receptor activation that can account for macroscopic as well as microscopic NMDA receptor properties.

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Figure 1: Burst properties of individual NMDA receptor activations.
Figure 2: Macroscopic properties of NR1/NR2B NMDA receptors.
Figure 3: Subunit-dependent contributions to NMDA receptor gating.
Figure 4: A model of NMDA receptor activation showing binding and activation of NMDA receptors, incorporating structural ideas about the pore region of the potassium channel31,32 and the GluR2 agonist binding pocket22,33.
Figure 5: A physical model of NMDA receptor activation.
Figure 6: Simulated responses to glycine and glutamate partial agonists.

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Acknowledgements

We thank S. Heinemann for sharing NMDA receptor cDNAs and D. Colquhoun for helpful discussions and sharing of software. In addition, we thank T. Auerbach for helpful discussions, critical comments on the manuscript and for suggesting the experiments with partial agonists. We also thank K. Erreger, A. Gibb and S. Cull-Candy for providing helpful comments on the manuscript. This work was supported by an Alfred Benzon Foundation grant (T.B.), a Danish Medical Research Fellowship (T.B.) and the National Institutes of Health (NS36654, S.F.T.).

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

    Tue G. Banke & Stephen F. Traynelis

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Correspondence to Tue G. Banke.

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Banke, T., Traynelis, S. Activation of NR1/NR2B NMDA receptors. Nat Neurosci 6, 144–152 (2003). https://doi.org/10.1038/nn1000

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