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Research ArticleNeuropharmacology

Ethanol Inhibition of Constitutively Open N-Methyl-d-Aspartate Receptors

Minfu Xu, C. Thetford Smothers, James Trudell and John J. Woodward
Journal of Pharmacology and Experimental Therapeutics January 2012, 340 (1) 218-226; DOI: https://doi.org/10.1124/jpet.111.187179
Minfu Xu
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C. Thetford Smothers
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James Trudell
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John J. Woodward
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Abstract

N-Methyl-d-aspartate (NMDA) receptors gate a slow and calcium-rich component of the postsynaptic glutamate response. Like all ionotropic glutamate receptors, NMDA subunits contain a highly conserved motif (SYTANLAAF) in the transmembrane (TM) 3 domain that is critically involved in channel gating. Mutation of an alanine in this domain (A7; underlined above) results in constitutively open receptors that show reduced sensitivity to several allosteric modulators. In this study, we examined the effects of ethanol, a substance that inhibits NMDA currents via an unknown mechanism, on tonically active NMDA receptors expressed in human embryonic kidney 293 cells. Ethanol (100 mM) inhibited currents from GluN1(A7R)/GluN2A and GluN1(A7R)/GluN2B receptors by approximately 50%, whereas those from GluN1/GluN2B(A7R) receptors were reduced by less than 10%. In cysteine-substituted GluN1 and GluN2 A7 mutants, estimated ethanol IC50 values for agonist-gated currents were 101, 117, 103, and 69 mM for GluN1(A7C)/GluN2A, GluN1(A7C)/GluN2B, GluN1/GluN2A(A7C), and GluN1/GluN2B(A7C) receptors, respectively. After exposure to the thiol-modifying reagent 2-(trimethylammonium)ethyl methanethiosulfonate (MTSET), A7C mutants showed robust agonist-independent currents and reduced sensitivity to ethanol (IC50 values of 371, 256, 715, and 958 mM, respectively, as above). In contrast, cysteine modification of the ligand-binding domain resulted in constitutively open receptors that showed robust ethanol inhibition. Ethanol inhibition of MTSET-treated GluN1(A7C) receptors was further reduced by TM3/TM4 mutations previously shown to reduce ethanol sensitivity of agonist-gated receptors. Overall, these results show that ethanol affects NMDA receptor function at a site distal from agonist binding and appears to exert greater effects via perturbation of GluN2 subunits.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grants R37-AA009986, R01-AA013378].

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

    http://dx.doi.org/10.1124/jpet.111.187179.

  • ABBREVIATIONS:

    NMDA
    N-methyl-d-aspartate
    LBD
    ligand-binding domain
    TM
    transmembrane
    MTSET
    (2-(trimethylammonium)ethyl methanethiosulfonate)
    AP5
    2-amino-5-phosphonovaleric acid
    CI
    confidence interval.

  • Received August 23, 2011.
  • Accepted October 14, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 1
1 Jan 2012
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Research ArticleNeuropharmacology

Ethanol and NMDA Receptors

Minfu Xu, C. Thetford Smothers, James Trudell and John J. Woodward
Journal of Pharmacology and Experimental Therapeutics January 1, 2012, 340 (1) 218-226; DOI: https://doi.org/10.1124/jpet.111.187179

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Research ArticleNeuropharmacology

Ethanol and NMDA Receptors

Minfu Xu, C. Thetford Smothers, James Trudell and John J. Woodward
Journal of Pharmacology and Experimental Therapeutics January 1, 2012, 340 (1) 218-226; DOI: https://doi.org/10.1124/jpet.111.187179
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