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Characterisation of the human NMDA receptor subunit NR3A glycine binding site.
Neuropharmacology. 2007 Mar; 52(4):1151-9.N

Abstract

In this study, we characterise the binding site of the human N-methyl-d-aspartate (NMDA) receptor subunit NR3A. Saturation radioligand binding of the NMDA receptor agonists [(3)H]-glycine and [(3)H]-glutamate showed that only glycine binds to human NR3A (hNR3A) with high affinity (K(d)=535nM (277-793nM)). Eight amino acids, which correspond to amino acids that are critical for ligand binding to other NMDA receptor subunits, situated within the S1S2 predicted ligand binding domain of hNR3A were mutated, which resulted in complete or near complete loss of [(3)H]-glycine binding to hNR3A. The NMDA NR1 glycine site agonist d-serine and partial agonist HA-966 (3-amino-1-hydroxypyrrolid-2-one), similarly to glycine displaced [(3)H]-glycine monophasically, suggesting a single common binding site. However, neither the partial agonist d-cycloserine nor the antagonist 7-chlorokynurenic acid displaced [(3)H]-glycine. Using homology modelling, a model of the NR3A binding pocket was generated which we suggest can be used to identify candidate agonists and antagonists. Our data show that glycine is a ligand, and most probably the endogenous ligand, for native NR3A at a binding site with unique pharmacological characteristics.

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Authors+Show Affiliations

Nilsson A
Division of Neurodegeneration and Neuroinflammation, Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Novum, S-141 86 Stockholm, Sweden. anna.nilsson.2@ki.se
Duan J
No affiliation info available
Mo-Boquist LL
No affiliation info available
Benedikz E
No affiliation info available
Sundström E
No affiliation info available

MeSH

AnimalsBinding, CompetitiveBrainCell Line, TransformedCycloserineDose-Response Relationship, DrugExcitatory Amino Acid AntagonistsGlycineHumansKynurenic AcidModels, MolecularMutationProtein BindingRatsReceptors, N-Methyl-D-AspartateTransfection

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17320117

Citation

Nilsson, A, et al. "Characterisation of the Human NMDA Receptor Subunit NR3A Glycine Binding Site." Neuropharmacology, vol. 52, no. 4, 2007, pp. 1151-9.
Nilsson A, Duan J, Mo-Boquist LL, et al. Characterisation of the human NMDA receptor subunit NR3A glycine binding site. Neuropharmacology. 2007;52(4):1151-9.
Nilsson, A., Duan, J., Mo-Boquist, L. L., Benedikz, E., & Sundström, E. (2007). Characterisation of the human NMDA receptor subunit NR3A glycine binding site. Neuropharmacology, 52(4), 1151-9.
Nilsson A, et al. Characterisation of the Human NMDA Receptor Subunit NR3A Glycine Binding Site. Neuropharmacology. 2007;52(4):1151-9. PubMed PMID: 17320117.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterisation of the human NMDA receptor subunit NR3A glycine binding site. AU - Nilsson,A, AU - Duan,J, AU - Mo-Boquist,L-L, AU - Benedikz,E, AU - Sundström,E, Y1 - 2006/12/22/ PY - 2006/05/12/received PY - 2006/12/05/revised PY - 2006/12/07/accepted PY - 2007/2/27/pubmed PY - 2007/6/2/medline PY - 2007/2/27/entrez SP - 1151 EP - 9 JF - Neuropharmacology JO - Neuropharmacology VL - 52 IS - 4 N2 - In this study, we characterise the binding site of the human N-methyl-d-aspartate (NMDA) receptor subunit NR3A. Saturation radioligand binding of the NMDA receptor agonists [(3)H]-glycine and [(3)H]-glutamate showed that only glycine binds to human NR3A (hNR3A) with high affinity (K(d)=535nM (277-793nM)). Eight amino acids, which correspond to amino acids that are critical for ligand binding to other NMDA receptor subunits, situated within the S1S2 predicted ligand binding domain of hNR3A were mutated, which resulted in complete or near complete loss of [(3)H]-glycine binding to hNR3A. The NMDA NR1 glycine site agonist d-serine and partial agonist HA-966 (3-amino-1-hydroxypyrrolid-2-one), similarly to glycine displaced [(3)H]-glycine monophasically, suggesting a single common binding site. However, neither the partial agonist d-cycloserine nor the antagonist 7-chlorokynurenic acid displaced [(3)H]-glycine. Using homology modelling, a model of the NR3A binding pocket was generated which we suggest can be used to identify candidate agonists and antagonists. Our data show that glycine is a ligand, and most probably the endogenous ligand, for native NR3A at a binding site with unique pharmacological characteristics. SN - 0028-3908 UR - https://www.unboundmedicine.com/medline/citation/17320117/Characterisation_of_the_human_NMDA_receptor_subunit_NR3A_glycine_binding_site_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(06)00411-4 DB - PRIME DP - Unbound Medicine ER -