Ligand-specific conformational changes in the α1 glycine receptor ligand-binding domain

Pless, Stephan A. and Lynch, Joseph W. (2009) Ligand-specific conformational changes in the α1 glycine receptor ligand-binding domain. The Journal of Biological Chemistry, 284 23: 15847-15856. doi:10.1074/jbc.M809343200

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Author Pless, Stephan A.
Lynch, Joseph W.
Title Ligand-specific conformational changes in the α1 glycine receptor ligand-binding domain
Journal name The Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2009-06-05
Year available 2009
Sub-type Article (original research)
DOI 10.1074/jbc.M809343200
Open Access Status File (Publisher version)
Volume 284
Issue 23
Start page 15847
End page 15856
Total pages 10
Editor Herbert Tabor
Place of publication Pike, Bethesda, U.S.A.
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Subject 110903 Central Nervous System
920111 Nervous System and Disorders
Abstract Understanding the activation mechanism of Cys loop ion channel receptors is key to understanding their physiological and pharmacological properties under normal and pathological conditions. The ligand-binding domains of these receptors comprise inner and outer β-sheets and structural studies indicate that channel opening is accompanied by conformational rearrangements in both β-sheets. In an attempt to resolve ligand-dependent movements in the ligand-binding domain, we employed voltage-clamp fluorometry on α1 glycine receptors to compare changes mediated by the agonist, glycine, and by the antagonist, strychnine. Voltage-clamp fluorometry involves labeling introduced cysteines with environmentally sensitive fluorophores and inferring structural rearrangements from ligand-induced fluorescence changes. In the inner β-sheet, we labeled residues in loop 2 and in binding domain loops D and E. At each position, strychnine and glycine induced distinct maximal fluorescence responses. The pre-M1 domain responded similarly; at each of four labeled positions glycine produced a strong fluorescence signal, whereas strychnine did not. This suggests that glycine induces conformational changes in the inner β-sheet and pre-M1 domain that may be important for activation, desensitization, or both. In contrast, most labeled residues in loops C and F yielded fluorescence changes identical in magnitude for glycine and strychnine. A notable exception was H201C in loop C. This labeled residue responded differently to glycine and strychnine, thus underlining the importance of loop C in ligand discrimination. These results provide an important step toward mapping the domains crucial for ligand discrimination in the ligand-binding domain of glycine receptors and possibly other Cys loop receptors.
Keyword Nicotinic acetylcholine-receptor
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
Queensland Brain Institute Publications
ERA 2012 Admin Only
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Citation counts: TR Web of Science Citation Count  Cited 43 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 07 Jul 2009, 22:57:42 EST by Debra McMurtrie on behalf of Queensland Brain Institute