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Author Notes:

Address correspondence to: Stephen F. Traynelis, Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Rollins Research Center, Atlanta, GA 30322; Email: strayne@emory.edu

Hiro Furukawa, Cold Spring Harbor Laboratory, Keck Structural Biology Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724; Email: furukawa@cshl.edu

Participated in research design: Hansen, Tajima, Perszyk, Vance, Ogden, Furukawa, Traynelis.

Conducted experiments: Hansen, Tajima, Perszyk, Vance, Ogden, Furukawa.

Contributed new reagents or analytic tools: Risgaard, Jørgensen, Clausen.

Performed data analysis: Hansen, Tajima, Perszyk, Vance, Ogden, Furukawa.

Wrote or contributed to the writing of the manuscript: Hansen, Tajima, Risgaard, Perszyk, Jørgensen, Vance, Ogden, Clausen, Furukawa, Traynelis.

The authors thank Phoung Le, Jing Zhang, and Anel Tankovic for excellent technical assistance.

They also thank the staff at X25 at the National Synchrotron Light Source at Brookhaven National Laboratory for beamline support.


Research Funding:

This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS036654 and NS065371]

The National Institutes of Health National Institute of Mental Health [Grant MH085926]

The National Institutes of Health National Institute of Environmental Health Sciences [Grant T32-ES012870]

The Robertson Research Fund of Cold Spring Harbor Laboratory

The Villum Kann Rasmussen Foundation

The Lundbeck Foundation

The Japan Society for the Promotion of Science

Structural Determinants of Agonist Efficacy at the Glutamate Binding Site of N-Methyl-d-Aspartate Receptors


Journal Title:

Molecular Pharmacology


Volume 84, Number 1


, Pages 114-127

Type of Work:

Article | Post-print: After Peer Review


N-methyl-d-aspartate (NMDA) receptors are ligand-gated ion channels assembled from GluN1 and GluN2 subunits. We used a series of N-hydroxypyrazole-5-glycine (NHP5G) partial agonists at the GluN2 glutamate binding site as tools to study activation of GluN1/GluN2A and GluN1/GluN2D NMDA receptor subtypes. Using two-electrode voltage-clamp electrophysiology, fast-application patch-clamp, and single-channel recordings, we show that propyl- and ethyl-substituted NHP5G agonists have a broad range of agonist efficacies relative to the full agonist glutamate (<1–72%). Crystal structures of the agonist binding domains (ABDs) of GluN2A and GluN2D do not reveal any differences in the overall domain conformation induced by binding of the full agonist glutamate or the partial agonist propyl-NHP5G, which is strikingly different from ABD structures of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoate (AMPA) and kainate receptors bound to full and partial agonists. Subsequent evaluation of relative NHP5G agonist efficacy at GluN2A-GluN2D chimeric subunits implicates the amino-terminal domain (ATD) as a strong determinant of agonist efficacy, suggesting that interdomain interactions between the ABD and the ATD may be a central element in controlling the manner by which agonist binding leads to channel opening. We propose that variation in the overall receptor conformation, which is strongly influenced by the nature of interdomain interactions in resting and active states, mediates differences in agonist efficacy and partial agonism at the GluN2 subunits.

Copyright information:

© 2013 by The American Society for Pharmacology and Experimental Therapeutics

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