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J. Biol. Chem., Vol. 279, Issue 19, 19559-19565, May 7, 2004

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Comparison of Taurine- and Glycine-induced Conformational Changes in the M2-M3 Domain of the Glycine Receptor^*

Nian-Lin R. Han, John D. Clements¶||, and Joseph W. Lynch**

From the School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072 and ^¶Division of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia

In the ionotropic glutamate receptor, the global conformational changes induced by partial agonists are smaller than those induced by full agonists. However, in the pentameric ligand-gated ion channel receptor family, the structural basis of partial agonism is not understood. This study investigated whether full and partial agonists induce different conformation changes in the glycine receptor chloride channel (GlyR). A substituted cysteine accessibility analysis demonstrated previously that glycine binding induced an increase in surface accessibility of all residues from Arg²⁷¹ to Lys²⁷⁶ in the M2-M3 domain of the homomeric 1 GlyR. Here we compare the surface accessibility changes induced by the full agonist, glycine, and the partial agonist, taurine. In GlyRs incorporating the A272C, S273C, L274C, or P275C mutation, the reaction rate of the cysteine-specific compound, methanethiosulfonate ethyltrimethylammonium, depended on how strongly the receptors were activated but was agonist-independent. Reaction rates could not be compared in the R271C and K276C mutant GlyRs because methanethiosulfonate ethyltrimethylammonium did not modify the extremely small currents induced by saturating taurine or equivalent low glycine concentrations. The results indicate that bound taurine and glycine molecules impose identical conformational changes to the M2-M3 domain. We therefore conclude that the higher efficacy of glycine is due to an increased ability to stabilize a common activated configuration.

Received for publication, January 18, 2004 , and in revised form, February 19, 2004.

^* This work was supported in part by the Australian Research Council. 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.

Recipient of an International Postgraduate Studentship from the Australian Commonwealth Department of Education, Training, and Youth Affairs. Present address: Dept. of Biological Sciences, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260.

^|| Supported by an Australian Research Council Senior Research Fellowship.

^** To whom correspondence should be addressed: School of Biomedical Sciences, University of Queensland, Brisbane QLD 4072, Australia. Tel.: 617-3365-3157; Fax: 617-3365-1766; E-mail: j.lynch{at}uq.edu.au.

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				S. A. Pless, M. I. Dibas, H. A. Lester, and J. W. Lynch Conformational Variability of the Glycine Receptor M2 Domain in Response to Activation by Different Agonists J. Biol. Chem., December 7, 2007; 282(49): 36057 - 36067. [Abstract] [Full Text] [PDF]