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Originally published In Press as doi:10.1074/jbc.M111356200 on December 13, 2001

J. Biol. Chem., Vol. 277, Issue 11, 9112-9117, March 15, 2002
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Identification of a Novel Residue within the Second Transmembrane Domain That Confers Use-facilitated Block by Picrotoxin in Glycine alpha 1 Receptors*

Mohammed I. Dibas, Eric B. Gonzales, Paromita Das, Cathy L. Bell-Horner, and Glenn H. DillonDagger

From the Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107

The central nervous system convulsant picrotoxin (PTX) inhibits GABAA and glutamate-gated Cl- channels in a use-facilitated fashion, whereas PTX inhibition of glycine and GABAC receptors displays little or no use-facilitated block. We have identified a residue in the extracellular aspect of the second transmembrane domain that converted picrotoxin inhibition of glycine alpha 1 receptors from non-use-facilitated to use-facilitated. In wild type alpha 1 receptors, PTX inhibited glycine-gated Cl- current in a competitive manner and had equivalent effects on peak and steady-state currents, confirming a lack of use-facilitated block. Mutation of the second transmembrane domain 15'-serine to glutamine (alpha 1(S15'Q) receptors) converted the mechanism of PTX blockade from competitive to non-competitive. However, more notable was the fact that in alpha 1(S15'Q) receptors, PTX had insignificant effects on peak current amplitude and dramatically enhanced current decay kinetics. Similar results were found in alpha 1(S15'N) receptors. The reciprocal mutation in the beta 2 subunit of alpha 1beta 2 GABAA receptors (alpha 1beta 2(N15'S) receptors) decreased the magnitude of use-facilitated PTX inhibition. Our results implicate a specific amino acid at the extracellular aspect of the ion channel in determining use-facilitated characteristics of picrotoxin blockade. Moreover, the data are consistent with the suggestion that picrotoxin may interact with two domains in ligand-gated anion channels.

* This work was supported by National Institutes Health Grant ES 07904 (to G. H. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107. Tel.: 817-735-2055; Fax: 817-735-2091; E-mail: gdillon@hsc.unt.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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