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Molecular Pharmacology

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Research ArticleArticle

A Novel Alcohol-Sensitive Position in the N-Methyl-d-Aspartate Receptor GluN2A Subunit M3 Domain Regulates Agonist Affinity and Ion Channel Gating

Hong Ren, Yulin Zhao, Man Wu and Robert W. Peoples
Molecular Pharmacology October 2013, 84 (4) 501-510; DOI: https://doi.org/10.1124/mol.113.085993
Hong Ren
Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin
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Yulin Zhao
Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin
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Man Wu
Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin
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Robert W. Peoples
Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin
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Abstract

Abundant evidence supports a role for N-methyl-d-aspartate (NMDA) receptor inhibition in the behavioral actions of ethanol, but the underlying molecular mechanisms have not been fully elucidated. We recently found that clusters of five positions in the third and fourth membrane-associated domains (M3 and M4) at the intersubunit interfaces form putative sites of alcohol action. In the present study, we found that one of these positions, NMDA receptor subunit, GluN2A(F636), can strongly regulate ethanol sensitivity, glutamate potency, and apparent desensitization: ethanol IC50 values, peak (Ip) and steady-state (Iss) glutamate EC50 values, and steady-state to peak current ratio (Iss:Ip) values differed significantly among the mutants tested. Changes in glutamate affinity among the various mutants were not attributable to agonist trapping due to desensitization, as glutamate peak EC50 values were correlated with values of both steady-state EC50 and Iss:Ip. The mean open times determined in selected mutants could be altered up to 4-fold but did not account for the changes in ethanol sensitivity. Ethanol sensitivity was significantly correlated with glutamate EC50 and Iss:Ip values, but the changes in ethanol IC50 among mutants at this position do not appear to be secondary to changes in ion channel kinetics. Substitution of the isomeric amino acids leucine and isoleucine had markedly different effects on ethanol sensitivity, agonist potency, and desensitization, which is consistent with a stringent structural requirement for ion channel modulation by the side chain at this position. Our results indicate that GluN2A(F636) plays an important role in both channel function and ethanol inhibition in NMDA receptors.

Footnotes

    • Received March 1, 2013.
    • Accepted July 11, 2013.
  • This work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grants AA015203-01A1 and AA015203-06A1] (to R.W.P.).

  • dx.doi.org/10.1124/mol.113.085993.

  • 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

NMDA Receptor M3 Domain Alcohol Sensitivity and Gating

Hong Ren, Yulin Zhao, Man Wu and Robert W. Peoples
Molecular Pharmacology October 1, 2013, 84 (4) 501-510; DOI: https://doi.org/10.1124/mol.113.085993

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Research ArticleArticle

NMDA Receptor M3 Domain Alcohol Sensitivity and Gating

Hong Ren, Yulin Zhao, Man Wu and Robert W. Peoples
Molecular Pharmacology October 1, 2013, 84 (4) 501-510; DOI: https://doi.org/10.1124/mol.113.085993
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