HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 49, 48815-48820, December 5, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/49/48815    most recent M302097200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ren, H. Articles by Peoples, R. W. Search for Related Content PubMed PubMed Citation Articles by Ren, H. Articles by Peoples, R. W. Social Bookmarking                      What's this?

A Site of Alcohol Action in the Fourth Membrane-associated Domain of the N-Methyl-D-aspartate Receptor^*

Hong Ren, Yumiko Honse, and Robert W. Peoples

From the Unit on Cellular Neuropharmacology, Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-8205

The N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptor is an important mediator of the behavioral effects of ethanol in the central nervous system. Although ethanol is known to inhibit NMDA receptors by influencing ion-channel gating, its molecular site of action and the mechanism underlying this effect have not been established. We have previously identified a conserved methionine residue in the fourth membrane-associated domain of the NMDA receptor NR2A subunit (Met⁸²³) that influences desensitization and gating of the ion channel. Here we report that this residue plays an important role in mediating the effect of ethanol on the NMDA receptor. Ethanol IC₅₀ values among functional substitution mutants at this position varied over the range 130–225 mM. There was a weak correlation between ethanol IC₅₀ and mean open time of NR2A(Met⁸²³) mutants that was dependent on inclusion of the value for the tryptophan mutant. In the absence of this value, there was no trend toward a correlation among the remaining mutants. Desensitization appeared to influence the action of ethanol, because ethanol IC₅₀ of the mutants was correlated with the steadystate to peak current ratio. With the exception of tryptophan, ethanol sensitivity was significantly related to the molecular volume and hydrophobicity of the substituent. The relation between ethanol sensitivity and the molecular volume and hydrophobicity at this position suggests that this residue interacts with or forms part of a site of ethanol action and that the presence of a tryptophan residue in this site disrupts its ability to interact with ethanol.

Received for publication, February 27, 2003 , and in revised form, September 18, 2003.

^* This research was supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism. The costs of publication of this article were defrayed in part by the payment of page charges. This 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 Biomedical Sciences, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881. Tel.: 414-288-6678; Fax: 414-288-6564; E-mail: robert.peoples{at}marquette.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Spanagel Alcoholism: A Systems Approach From Molecular Physiology to Addictive Behavior Physiol Rev, April 1, 2009; 89(2): 649 - 705. [Abstract] [Full Text] [PDF]

				O. Desy, D. Carignan, M. Caruso, and P. O. de Campos-Lima Immunosuppressive Effect of Isopropanol: Down-Regulation of Cytokine Production Results from the Alteration of Discrete Transcriptional Pathways in Activated Lymphocytes J. Immunol., August 15, 2008; 181(4): 2348 - 2355. [Abstract] [Full Text] [PDF]

				H. Ren, A. K. Salous, J. M. Paul, K. A. Lamb, D. S. Dwyer, and R. W. Peoples Functional Interactions of Alcohol-sensitive Sites in the N-Methyl-D-aspartate Receptor M3 and M4 Domains J. Biol. Chem., March 28, 2008; 283(13): 8250 - 8257. [Abstract] [Full Text] [PDF]