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J. Biol. Chem. 278 (38): 36669-36675

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Synaptic PDZ Domain-mediated Protein Interactions Are Disrupted by Inhalational Anesthetics*

Ming Fang {ddagger}, Yuan-Xiang Tao {ddagger}, Fahu He §, Mingjie Zhang §, Claire F. Levine {ddagger}, Peizhong Mao {ddagger}, Feng Tao {ddagger}, Chih-Ling Chou ¶, Scheherazade Sadegh-Nasseri ¶, and Roger A. Johns {ddagger} ||

Departments of {ddagger}Anesthesiology and Critical Care Medicine and Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287 and the §Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

Abstract: Anesthetics exert multiple effects on the central nervous system through altering synaptic transmission, but the mechanisms for this process are poorly understood. PDZ domain-mediated protein interactions play a central role in organizing signaling complexes around synaptic receptors for efficient signal transduction. We report here that clinically relevant concentrations of inhalational anesthetics dose-dependently and specifically inhibit the PDZ domain-mediated protein interaction between PSD-95 or PSD-93 and the N-methyl-D-aspartate receptor or neuronal nitric-oxide synthase. These inhibitory effects are immediate, potent, and reversible and occur at a hydrophobic peptide-binding groove on the surface of the second PDZ domain of PSD-95 in a manner relevant to anesthetic action. These findings reveal the PDZ domain as a new molecular target for inhalational anesthetics.

Received for publication April 4, 2003. Revision received July 1, 2003.

* This work was supported by National Institutes of Health Grants GM49111 and NS 44219 (to R. A. J.) and the Johns Hopkins University Blaustein Pain Research Fund (to Y.-X. T.). 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 Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Ross 361, 720 Rutland Ave., Baltimore, MD 21205. Tel.: 410-614-1848; Fax: 410-614-7711; E-mail: Rajohns{at}jhmi.edu.

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