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Molecular Pharmacology

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Research ArticleArticle

Ifenprodil Effects on GluN2B-Containing Glutamate Receptors

Stacy A. Amico-Ruvio, Meaghan A. Paganelli, Jason M. Myers and Gabriela K. Popescu
Molecular Pharmacology December 2012, 82 (6) 1074-1081; DOI: https://doi.org/10.1124/mol.112.078998
Stacy A. Amico-Ruvio
Department of Biochemistry (S.A.A., J.M.M., G.K.P.) and Neuroscience Program (M.A.P., G.K.P.), School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
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Meaghan A. Paganelli
Department of Biochemistry (S.A.A., J.M.M., G.K.P.) and Neuroscience Program (M.A.P., G.K.P.), School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
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Jason M. Myers
Department of Biochemistry (S.A.A., J.M.M., G.K.P.) and Neuroscience Program (M.A.P., G.K.P.), School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
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Gabriela K. Popescu
Department of Biochemistry (S.A.A., J.M.M., G.K.P.) and Neuroscience Program (M.A.P., G.K.P.), School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
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Abstract

N-Methyl-d-aspartate (NMDA) receptors are glutamate- and glycine-gated channels that mediate fast excitatory transmission in the central nervous system and are critical to synaptic development, plasticity, and integration. They have a rich complement of modulatory sites, which represent important pharmacological targets. Ifenprodil is a well tolerated NMDA receptor inhibitor; it is selective for GluN2B-containing receptors and has neuroprotective effects. The mechanism by which ifenprodil inhibits NMDA receptor responses is not fully understood. The inhibition is incomplete and noncompetitive with other known NMDA receptor agonists or modulators, although reciprocal effects have been reported between ifenprodil potency and that of extracellular ligands including glutamate, glycine, zinc, protons, and polyamines. Recent structural studies revealed that ifenprodil binds to a unique site at the interface between the extracellular N termini of GluN1 and GluN2B subunits, supporting the view that interactions with other extracellular modulators are indirect. In this study, we examined how ifenprodil affects the gating reaction of NMDA receptors in conditions designed to minimize actions by contemporaneous ligands. We found that ifenprodil decreased NMDA receptor equilibrium open probability by raising an energetic barrier to activation and also by biasing the receptor toward low open probability gating modes. These results demonstrate intrinsic effects of ifenprodil on NMDA receptor stationary gating kinetics and provide means to anticipate how ifenprodil will affect receptor responses in defined physiological and pathological circumstances.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant 052669].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.078998.

  • ABBREVIATIONS:

    NMDA
    N-methyl-d-aspartate
    2B
    GluN2B
    NTD
    N-terminal domain
    LBD
    ligand-binding domain
    HEPBS
    N-(2-hydroxyethyl) piperazine-N′-(4-butanesulfonic acid)
    IFN
    ifenprodil
    CTR
    control
    MCT
    mean closed time
    MOT
    mean open time.

  • Received March 28, 2012.
  • Accepted August 30, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (6)
Molecular Pharmacology
Vol. 82, Issue 6
1 Dec 2012
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Research ArticleArticle

Ifenprodil Modulation of 2B Receptors

Stacy A. Amico-Ruvio, Meaghan A. Paganelli, Jason M. Myers and Gabriela K. Popescu
Molecular Pharmacology December 1, 2012, 82 (6) 1074-1081; DOI: https://doi.org/10.1124/mol.112.078998

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Research ArticleArticle

Ifenprodil Modulation of 2B Receptors

Stacy A. Amico-Ruvio, Meaghan A. Paganelli, Jason M. Myers and Gabriela K. Popescu
Molecular Pharmacology December 1, 2012, 82 (6) 1074-1081; DOI: https://doi.org/10.1124/mol.112.078998
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