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J. Biol. Chem., Vol. 281, Issue 6, 3305-3311, February 10, 2006

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Occupancy of a Single Anesthetic Binding Pocket Is Sufficient to Enhance Glycine Receptor Function^*

From the Waggoner Center for Alcohol and Addiction Research, Section of Neurobiology, Institutes for Neuroscience and Cell and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712

Alcohols and volatile anesthetics enhance the function of inhibitory glycine receptors (GlyRs). This is hypothesized to occur by their binding to a pocket formed between the transmembrane domains of individual 1 GlyR subunits. Because GlyRs are pentameric, it follows that each GlyR contains up to five alcohol/anesthetic binding sites, with one in each subunit. We asked how many subunits per pentamer need be bound by drug in order to enhance receptor-mediated currents. A cysteine mutation was introduced at amino acid serine 267 (S267C) in the transmembrane 2 domain as a tool to block GlyR potentiation by some anesthetic drugs and to provide a means for covalent binding by the small, anesthetic-like thiol reagent propyl methanethiosulfonate. Xenopus laevis oocytes were co-injected with various ratios of wild-type (wt) to S267C 1 GlyR cDNAs in order to express heteromeric receptors with a range of wt:mutant subunit stoichiometries. The enhancement of GlyR currents by 200 mM ethanol and 1.5 mM chloroform was positively correlated with the number of wt subunits found in heteromeric receptors. Furthermore, currents from oocytes injected with high ratios of wt to S267C cDNAs (up to 200:1) were significantly and irreversibly enhanced following propyl methanethiosulfonate labeling and washout, demonstrating that drug binding to a single subunit in the receptor pentamer is sufficient to induce enhancement of GlyR currents.

Received for publication, February 22, 2005 , and in revised form, November 16, 2005.

^* This work was supported by National Institutes of Health Grants R01 AA11525 and P01 GM47818 (to S. J. M.) and F31 AA14454 (to M. T. R.). 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.

¹ To whom correspondence should be addressed: The University of Texas at Austin, 1 University Station A4800, Austin, TX 78712-0159. Tel.: 512-232-7174; Fax: 512-232-2525; E-mail: mihic{at}mail.utexas.edu.

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