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Interactions between ifenprodil and the NR2B subunit of the N-methyl-D-aspartate receptor.
J Biol Chem. 1996 Apr 19; 271(16):9603-11.JB

Abstract

Ifenprodil is an atypical noncompetitive modulator of the N-methyl-D-aspartate (NMDA) receptor (NR) which demonstrates a 140-fold preference for NR2B over NR2A subunits, although the molecular basis for this subunit specificity is unknown. We have made chimeric receptors by fusing the murine forms of NR2A (epsilon 1) and NR2B (epsilon 2) to localize the high affinity determinants of ifenprodil inhibition on the 2B subunit. Binding experiments with 125I-MK-801 implicated the region between amino acids 198 and 356 of NR2B for high affinity ifenprodil interaction. Site-directed mutants at Arg-337 showed that this residue is absolutely required for high affinity ifenprodil inhibition. Polyamines also modulate the NMDA receptor with a preference for NR2B subunits, and the pharmacology of these agents overlaps with ifenprodil. Although the determinants of the polyamine enhancement of iodo-MK-801 binding also localize to the NH2 terminus of NR2B, the point mutants at Arg-337 form receptors that are polyamine-stimulated at wild type levels. In addition, polyamine stimulation depends on the expression of NR1 splice variants, whereas high affinity ifenprodil inhibition is independent of NR1 isoform expression. These studies provide evidence that ifenprodil and polyamines interact at discrete sites on the NR2B subunit.

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Authors+Show Affiliations

Gallagher MJ
Department of Neurology, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Huang H
No affiliation info available
Pritchett DB
No affiliation info available
Lynch DR
No affiliation info available

MeSH

Alternative SplicingAmino Acid SequenceAnimalsArginineBase SequenceBinding SitesCell LineCloning, MolecularDNA PrimersDizocilpine MaleateExcitatory Amino Acid AntagonistsGenetic VariationHumansKidneyKineticsMacromolecular SubstancesMiceMolecular Sequence DataMutagenesis, Site-DirectedPiperidinesPolymerase Chain ReactionReceptors, N-Methyl-D-AspartateRecombinant Fusion ProteinsSpermidineTransfection

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8621635

Citation

Gallagher, M J., et al. "Interactions Between Ifenprodil and the NR2B Subunit of the N-methyl-D-aspartate Receptor." The Journal of Biological Chemistry, vol. 271, no. 16, 1996, pp. 9603-11.
Gallagher MJ, Huang H, Pritchett DB, et al. Interactions between ifenprodil and the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem. 1996;271(16):9603-11.
Gallagher, M. J., Huang, H., Pritchett, D. B., & Lynch, D. R. (1996). Interactions between ifenprodil and the NR2B subunit of the N-methyl-D-aspartate receptor. The Journal of Biological Chemistry, 271(16), 9603-11.
Gallagher MJ, et al. Interactions Between Ifenprodil and the NR2B Subunit of the N-methyl-D-aspartate Receptor. J Biol Chem. 1996 Apr 19;271(16):9603-11. PubMed PMID: 8621635.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interactions between ifenprodil and the NR2B subunit of the N-methyl-D-aspartate receptor. AU - Gallagher,M J, AU - Huang,H, AU - Pritchett,D B, AU - Lynch,D R, PY - 1996/4/19/pubmed PY - 1996/4/19/medline PY - 1996/4/19/entrez SP - 9603 EP - 11 JF - The Journal of biological chemistry JO - J Biol Chem VL - 271 IS - 16 N2 - Ifenprodil is an atypical noncompetitive modulator of the N-methyl-D-aspartate (NMDA) receptor (NR) which demonstrates a 140-fold preference for NR2B over NR2A subunits, although the molecular basis for this subunit specificity is unknown. We have made chimeric receptors by fusing the murine forms of NR2A (epsilon 1) and NR2B (epsilon 2) to localize the high affinity determinants of ifenprodil inhibition on the 2B subunit. Binding experiments with 125I-MK-801 implicated the region between amino acids 198 and 356 of NR2B for high affinity ifenprodil interaction. Site-directed mutants at Arg-337 showed that this residue is absolutely required for high affinity ifenprodil inhibition. Polyamines also modulate the NMDA receptor with a preference for NR2B subunits, and the pharmacology of these agents overlaps with ifenprodil. Although the determinants of the polyamine enhancement of iodo-MK-801 binding also localize to the NH2 terminus of NR2B, the point mutants at Arg-337 form receptors that are polyamine-stimulated at wild type levels. In addition, polyamine stimulation depends on the expression of NR1 splice variants, whereas high affinity ifenprodil inhibition is independent of NR1 isoform expression. These studies provide evidence that ifenprodil and polyamines interact at discrete sites on the NR2B subunit. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/8621635/Interactions_between_ifenprodil_and_the_NR2B_subunit_of_the_N_methyl_D_aspartate_receptor_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(17)31379-0 DB - PRIME DP - Unbound Medicine ER -