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Identification of amino acids in the N-methyl-D-aspartate receptor NR1 subunit that contribute to the glycine binding site.
Mol Pharmacol. 1995 Feb; 47(2):374-80.MP

Abstract

The mammalian N-methyl-D-aspartate (NMDA) receptor complex is though to consist of an NR1 subunit in combination with one or more of the four NR2 subunits (A, B, C, and D). When corresponding cDNAs are expressed in Xenopus oocytes, ion channels with the characteristic profile of NMDA receptors are formed. The receptor is unique in requiring two coagonists, glutamate and glycine, for activation of the channel. We have used site-directed mutagenesis to study amino acids in the human NR1 subunit that contribute to the glycine binding site of the NMDA receptor without affecting the agonist site for glutamate. Mutations to D481 and K483 produced receptors with up to 160-fold lower affinities for glycine, as well as other agonists and partial agonists, without affecting maximum current size or the degree of agonist efficacy. The D481A mutation also led to 40-50-fold lower affinities for two structurally diverse glycine site antagonists. From these data we propose that the carboxyl group of this aspartate interacts with the amino moiety of glycine and the equivalent group contained in other agonists and antagonists.

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Authors+Show Affiliations

Wafford KA
Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Harlow, Essex, UK.
Kathoria M
No affiliation info available
Bain CJ
No affiliation info available
Marshall G
No affiliation info available
Le Bourdellès B
No affiliation info available
Kemp JA
No affiliation info available
Whiting PJ
No affiliation info available

MeSH

Amino Acid SequenceAmino AcidsAnimalsBinding SitesGlycineHumansMolecular Sequence DataMutationReceptors, N-Methyl-D-AspartateSequence Homology, Amino AcidXenopus

Pub Type(s)

Journal Article

Language

eng

PubMed ID

7870047

Citation

Wafford, K A., et al. "Identification of Amino Acids in the N-methyl-D-aspartate Receptor NR1 Subunit That Contribute to the Glycine Binding Site." Molecular Pharmacology, vol. 47, no. 2, 1995, pp. 374-80.
Wafford KA, Kathoria M, Bain CJ, et al. Identification of amino acids in the N-methyl-D-aspartate receptor NR1 subunit that contribute to the glycine binding site. Mol Pharmacol. 1995;47(2):374-80.
Wafford, K. A., Kathoria, M., Bain, C. J., Marshall, G., Le Bourdellès, B., Kemp, J. A., & Whiting, P. J. (1995). Identification of amino acids in the N-methyl-D-aspartate receptor NR1 subunit that contribute to the glycine binding site. Molecular Pharmacology, 47(2), 374-80.
Wafford KA, et al. Identification of Amino Acids in the N-methyl-D-aspartate Receptor NR1 Subunit That Contribute to the Glycine Binding Site. Mol Pharmacol. 1995;47(2):374-80. PubMed PMID: 7870047.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of amino acids in the N-methyl-D-aspartate receptor NR1 subunit that contribute to the glycine binding site. AU - Wafford,K A, AU - Kathoria,M, AU - Bain,C J, AU - Marshall,G, AU - Le Bourdellès,B, AU - Kemp,J A, AU - Whiting,P J, PY - 1995/2/1/pubmed PY - 1995/2/1/medline PY - 1995/2/1/entrez SP - 374 EP - 80 JF - Molecular pharmacology JO - Mol Pharmacol VL - 47 IS - 2 N2 - The mammalian N-methyl-D-aspartate (NMDA) receptor complex is though to consist of an NR1 subunit in combination with one or more of the four NR2 subunits (A, B, C, and D). When corresponding cDNAs are expressed in Xenopus oocytes, ion channels with the characteristic profile of NMDA receptors are formed. The receptor is unique in requiring two coagonists, glutamate and glycine, for activation of the channel. We have used site-directed mutagenesis to study amino acids in the human NR1 subunit that contribute to the glycine binding site of the NMDA receptor without affecting the agonist site for glutamate. Mutations to D481 and K483 produced receptors with up to 160-fold lower affinities for glycine, as well as other agonists and partial agonists, without affecting maximum current size or the degree of agonist efficacy. The D481A mutation also led to 40-50-fold lower affinities for two structurally diverse glycine site antagonists. From these data we propose that the carboxyl group of this aspartate interacts with the amino moiety of glycine and the equivalent group contained in other agonists and antagonists. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/7870047/Identification_of_amino_acids_in_the_N_methyl_D_aspartate_receptor_NR1_subunit_that_contribute_to_the_glycine_binding_site_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7870047 DB - PRIME DP - Unbound Medicine ER -