Molecular determinants of β-carboline inhibition of the glycine receptor

Chen, Xuebin, Cromer, Brett. A. and Lynch, Joseph W. (2009) Molecular determinants of β-carboline inhibition of the glycine receptor. Journal Of Neurochemistry, 110 5: 1685-1694. doi:10.1111/j.1471-4159.2009.06273.x

Author Chen, Xuebin
Cromer, Brett. A.
Lynch, Joseph W.
Title Molecular determinants of β-carboline inhibition of the glycine receptor
Journal name Journal Of Neurochemistry   Check publisher's open access policy
ISSN 0022-3042
Publication date 2009-09
Year available 2009
Sub-type Article (original research)
DOI 10.1111/j.1471-4159.2009.06273.x
Volume 110
Issue 5
Start page 1685
End page 1694
Total pages 10
Editor Sean Murphy
Tony J. Turner
Place of publication Oxford, U.K.
Publisher Blackwell
Collection year 2010
Language eng
Subject C1
110903 Central Nervous System
920111 Nervous System and Disorders
Formatted abstract
β-Carbolines are potent modulators of GABA type A receptors and they have recently been shown to inhibit glycine receptors in a subunit-specific manner. The present study screened four structurally similar β-carbolines, 1,2,3,4-tetrahydronorharmane, norharmane, harmane and 6-methoxyharmalan, at recombinantly expressed α1, α1β, α2 and α3 glycine receptors with the aims of identifying structural elements of both the receptor and the compounds that are important for binding and subunit specificity. The four compounds exhibited only weak subunit specificity, rendering them unsuitable as pharmacological probes. Because they displayed competitive antagonist activity, we investigated the roles of known glycine binding residues in coordinating the four compounds. The structural similarity of the compounds, coupled with the differential effects of C-loop mutations (T204A, F207Y) on compound potency, implied direct interactions between variable β-carboline groups and mutated residues. Mutant cycle analysis employing harmane and norharmane revealed a strong pairwise interaction between the harmane methyl group and the C-loop in the region T204 and F207. These results which define the orientation of the bound β-carbolines were supported by molecular docking simulations. The information may also be relevant to understanding the mechanism β-carboline of binding to GABA type A receptors where they are potent pharmacological probes.
© 2009 The Authors.
Keyword Binding site
Chloride channel
Cys-loop 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
School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 2 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 2 times in Scopus Article | Citations
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Created: Thu, 10 Sep 2009, 16:28:29 EST by Debra McMurtrie on behalf of Queensland Brain Institute