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J. Biol. Chem., Vol. 280, Issue 36, 31450-31459, September 9, 2005

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Ethanol Alters Trafficking and Functional N-Methyl-D-aspartate Receptor NR2 Subunit Ratio via H-Ras^*

Neesha Suvarna, Stephanie L. Borgland, Jun Wang, Khanhky Phamluong, Yves P. Auberson¶, Antonello Bonci||, and Dorit Ron||**

From the ^||Department of Neurology, University of California, San Francisco, California 94608, the ^¶Novartis Institute of BioMedical Research, Basel CH-4002, Switzerland, and the Ernest Gallo Research Center, Emeryville, California 94608

The N-methyl-D-aspartate receptor (NMDAR) plays a critical role in synaptic plasticity and is one of the main targets for alcohol (ethanol) in the brain. Trafficking of the NMDAR is emerging as a key regulatory mechanism that underlies channel activity and synaptic plasticity. Here we show that exposure of hippocampal neurons to ethanol increases the internalization of the NR2A but not NR2B subunit of the NMDAR via the endocytic pathway. We further observed that ethanol exposure results in NR2A endocytosis through the activation of H-Ras and the inhibition of the tyrosine kinase Src. Importantly, ethanol treatment alters functional subunit composition from NR2A/NR2B- to mainly NR2B-containing NMDARs. Our results suggest that addictive drugs such as ethanol alter NMDAR trafficking and subunit composition. This may be an important mechanism by which ethanol exerts its effects on NMDARs to produce alcohol-induced aberrant plasticity.

Received for publication, April 15, 2005 , and in revised form, July 8, 2005.

^* This work was supported by the National Institute on Alcohol Abuse and Alcoholism Grant RO1AA013438-03 (to D. R.) and the State of California for Medical Research on Alcohol and Substance Abuse through the University of California San Francisco (to D. R. and A. B.). 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.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Ernest Gallo Clinic and Research Center, 5858 Horton St., Suite 200, Emeryville, CA 94608. Tel.: 510-985-3150; Fax: 510-985-3101; E-mail: dorit{at}itsa.ucsf.edu.

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