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J. Biol. Chem., Vol. 279, Issue 32, 33919-33927, August 6, 2004

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Channel Gating of the Glycine Receptor Changes Accessibility to Residues Implicated in Receptor Potentiation by Alcohols and Anesthetics^*

Ingrid A. Lobo, Maria Paola Mascia¶, James R. Trudell||, and R. Adron Harris

From the Institute for Cellular and Molecular Biology, Waggoner Center for Alcohol and Addiction Research and Section of Neurobiology, The University of Texas, Austin, Texas 78712, the ^¶Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Department of Experimental Biology, University of Cagliari, 09123 Cagliari, Italy, and the ^||Department of Anesthesia, Stanford University School of Medicine, Stanford, California 94305

The glycine receptor is a target for both alcohols and anesthetics, and certain amino acids in the 1 subunit transmembrane segments (TM) are critical for drug effects. Introducing larger amino acids at these positions increases the potency of glycine, suggesting that introducing larger residues, or drug molecules, into the drug-binding cavity facilitates channel opening. A possible mechanism for these actions is that the volume of the cavity expands and contracts during channel opening and closing. To investigate this hypothesis, mutations for amino acids in TM1 (I229C) and TM2 (G256C, T259C, V260C, M263C, T264C, S267C, S270C) and TM3 (A288C) were individually expressed in Xenopus laevis oocytes. The ability of sulfhydryl-specific alkyl methanethiosulfonate (MTS) compounds of different lengths to covalently react with introduced cysteines in both the closed and open states of the receptor was determined. S267C was accessible to short chain (C3–C8) MTS in both open and closed states, but was only accessible to longer chain (C10–C16) MTS compounds in the open state. Reaction with S267C was faster in the open state. I229C and A288C showed state-dependent reaction with MTS only in the presence of agonist. M263C and S270C were also accessible to MTS labeling. Mutated residues more intracellular than M263C did not react, indicating a floor of the cavity. These data demonstrate that the conformational changes accompanying channel gating increase accessibility to amino acids critical for drug action in TM1, TM2, and TM3, which may provide a mechanism by which alcohols and anesthetics can act on glycine (and likely other) receptors.

Received for publication, December 19, 2003 , and in revised form, May 20, 2004.

^* This work was supported by National Institutes of Health Grants AA06399 (to R. A. H.), AA13378 (to J. R. T.), GM47818 (to R. A. H.), and AA13778 (to I. A. L.). 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. Tel.: 512-232-2487; Fax: 512-232-2525; E-mail: dirgni{at}mail.utexas.edu.

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