RGD Reference Report - Structural determinants of agonist efficacy at the glutamate binding site of N-methyl-D-aspartate receptors. - Rat Genome Database

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Structural determinants of agonist efficacy at the glutamate binding site of N-methyl-D-aspartate receptors.

Authors: Hansen, Kasper B  Tajima, Nami  Risgaard, Rune  Perszyk, Riley E  Jørgensen, Lars  Vance, Katie M  Ogden, Kevin K  Clausen, Rasmus P  Furukawa, Hiro  Traynelis, Stephen F 
Citation: Hansen KB, etal., Mol Pharmacol. 2013 Jul;84(1):114-27. doi: 10.1124/mol.113.085803. Epub 2013 Apr 26.
RGD ID: 13432339
Pubmed: PMID:23625947   (View Abstract at PubMed)
PMCID: PMC3684824   (View Article at PubMed Central)
DOI: DOI:10.1124/mol.113.085803   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
NMDA selective glutamate receptor complex part_ofIDA 13432339; 13432339PMID:23625947UniProt 
plasma membrane located_inIDA 13432339; 13432339PMID:23625947UniProt 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
NMDA glutamate receptor activity enablesIMP 13432339; 13432339PMID:23625947UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Grin2a  (glutamate ionotropic receptor NMDA type subunit 2A)
Grin2d  (glutamate ionotropic receptor NMDA type subunit 2D)


Additional Information