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J. Biol. Chem., Vol. 282, Issue 49, 36057-36067, December 7, 2007

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Conformational Variability of the Glycine Receptor M2 Domain in Response to Activation by Different Agonists^*

Stephan A. Pless¹, Mohammed I. Dibas², Henry A. Lester, and Joseph W. Lynch³

From the School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia and the Division of Biology, California Institute of Technology, Pasadena, California 91125

Models describing the structural changes mediating Cys loop receptor activation generally give little attention to the possibility that different agonists may promote activation via distinct M2 pore-lining domain structural rearrangements. We investigated this question by comparing the effects of different ligands on the conformation of the external portion of the homomeric 1 glycine receptor M2 domain. Conformational flexibility was assessed by tethering a rhodamine fluorophore to cysteines introduced at the 19' or 22' positions and monitoring fluorescence and current changes during channel activation. During glycine activation, fluorescence of the label attached to R19'C increased by 20%, and the emission peak shifted to lower wavelengths, consistent with a more hydrophobic fluorophore environment. In contrast, ivermectin activated the receptors without producing a fluorescence change. Although taurine and β-alanine were weak partial agonists at the 1R19'C glycine receptor, they induced large fluorescence changes. Propofol, which drastically enhanced these currents, did not induce a glycine-like blue shift in the spectral emission peak. The inhibitors strychnine and picrotoxin elicited fluorescence and current changes as expected for a competitive antagonist and an open channel blocker, respectively. Glycine and taurine (or β-alanine) also produced an increase and a decrease, respectively, in the fluorescence of a label attached to the nearby L22'C residue. Thus, results from two separate labeled residues support the conclusion that the glycine receptor M2 domain responds with distinct conformational changes to activation by different agonists.

Received for publication, August 6, 2007 , and in revised form, September 20, 2007.

^* This work was supported in part by the National Health and Medical Research Council of Australia and by National Institutes of Health Grant NS-11756. 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 Supported by an International Postgraduate Research Scholarship from the University of Queensland.

² Supported by an National Research Service Award from the National Institutes of Health.

³ Supported by a National Health and Medical Research Council of Australia Senior Research Fellowship. To whom correspondence should be addressed: School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia. Tel.: 617-3365-3157; Fax: 617-3365-1766; E-mail: j.lynch{at}uq.edu.au.

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