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Research ArticleArticle

Inhibition of GluN2A-Containing N-Methyl-d-Aspartate Receptors by 2-Naphthoic Acid

Han Yu and Gabriela K. Popescu
Molecular Pharmacology October 2013, 84 (4) 541-550; DOI: https://doi.org/10.1124/mol.113.087189
Han Yu
Neuroscience Program (H.Y., G.K.P.) and Department of Biochemistry (G.K.P.), School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
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Gabriela K. Popescu
Neuroscience Program (H.Y., G.K.P.) and Department of Biochemistry (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 mediate excitatory synaptic transmission in the central nervous system and play important roles in synaptic development and plasticity, but also mediate glutamate neurotoxicity. Recently, 2-naphthoic acid (NPA) and its derivatives have been identified as allosteric, noncompetitive NMDA receptor inhibitors. The selectivity of NPA derivatives among NMDA receptor subtypes was mapped structurally to the ligand-binding domain, and was proposed to be mediated by residues on the S1 segment. To delineate the kinetic mechanism by which NPA inhibits NMDA receptor activity, we examined its effects on the NMDA receptor gating reaction. Using whole-cell patch clamping on human embryonic kidney 293 cells expressing recombinant NMDA family of glutamate receptor subunits, GluN1/GluN2A, we found that NPA has a 50% inhibitory effect at 1.9 mM. Further, from one-channel current recordings, we found that 4 mM NPA caused a 62% decrease in open probability by decreasing mean open time 2.5-fold and by increasing mean closed time 2-fold. Kinetic modeling suggested that NPA binding stabilized NMDA receptor closed states and increased the energy barriers toward open states, causing NMDA receptors to dwell longer in pre-open states along the activation pathway. The reaction mechanisms we derived provide quantitative insight into the inhibitory mechanism of NPA and help anticipate its effects on GluN1/GluN2A receptors during both physiologic and pathologic activation modalities.

Footnotes

    • Received May 6, 2013.
    • Accepted July 19, 2013.
  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS052669].

  • dx.doi.org/10.1124/mol.113.087189.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (4)
Molecular Pharmacology
Vol. 84, Issue 4
1 Oct 2013
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Research ArticleArticle

2-Naphthoic Acid Modulation of NMDA Receptors

Han Yu and Gabriela K. Popescu
Molecular Pharmacology October 1, 2013, 84 (4) 541-550; DOI: https://doi.org/10.1124/mol.113.087189

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Research ArticleArticle

2-Naphthoic Acid Modulation of NMDA Receptors

Han Yu and Gabriela K. Popescu
Molecular Pharmacology October 1, 2013, 84 (4) 541-550; DOI: https://doi.org/10.1124/mol.113.087189
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