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Originally published In Press as doi:10.1074/jbc.M102800200 on September 25, 2001

J. Biol. Chem., Vol. 276, Issue 48, 44729-44735, November 30, 2001
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Ethanol Inhibition of N-Methyl-D-aspartate Receptors Is Reduced by Site-directed Mutagenesis of a Transmembrane Domain Phenylalanine Residue*

Kimberly M. Ronald, Tooraj MirshahiDagger , and John J. Woodward§

From the Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298 and Dagger  Department of Molecular Biophysics, Mt. Sinai School of Medicine, New York, New York 10029

N-Methyl-D-aspartate (NMDA) receptors (NRs) are ionotropic receptors activated by glutamate and the co-agonist glycine. Ethanol inhibits NMDA receptor function, although its site of action is undefined. We hypothesized that ethanol acts at specific amino acids contained within the transmembrane (TM) domains of the receptor. In this study, NR1 and NR2A subunits were altered by mutagenesis and tested for sensitivity to ethanol. Three NR1 mutants (W636A, F817A, and L819A) and one NR2A mutant (F637A) failed to generate functional receptors. Pre-TM1 (I546A, L551A, F554A, and F558A), TM1 (W563A), and TM2 (W611A) NR1 mutations did not affect ethanol sensitivity of heteromeric receptors. In contrast, altering a TM3 phenylalanine to alanine (F639A) reduced the ethanol inhibition of NMDA receptors expressed in oocytes and human embryonic kidney 293 cells. Mutation of the nearby methionine (M641) to alanine did not affect ethanol sensitivity, whereas changing Phe639 to tryptophan slightly enhanced ethanol inhibition. NR1(F639A) did not alter the agonist potency of glutamate but did produce a leftward shift in the glycine concentration response for receptors containing NR2A and NR2B subunits. NR1(F639A) also reduced the potency of the competitive glycine antagonist 5,7-dichlorokynurenic acid and increased the efficacy of the glycine partial agonist 3-amino-1-hydroxy-2-pyrrolidinone ((+)-HA-966). These results suggest that ethanol may interact with amino acids contained in the TM3 domain of NMDA subunits that are involved in transducing agonist binding to channel opening.

* This work was supported by R01-AA009986 and K02-AA00238 and T32-DA07027 (to K. M. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Dept. of Physiology and Neuroscience, Medical University of South Carolina, MUSC IOP 4N, P. O. Box 250861, Charleston, SC 29425.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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