The M4 transmembrane segment contributes to agonist efficacy differences between alpha1 and alpha3 glycine receptors

Chen, Xuebin, Webb, Timothy I. and Lynch, Joseph W. (2009) The M4 transmembrane segment contributes to agonist efficacy differences between alpha1 and alpha3 glycine receptors. Molecular Membrane Biology, 26 5-7: 321-332. doi:10.1080/09687680903120319


Author Chen, Xuebin
Webb, Timothy I.
Lynch, Joseph W.
Title The M4 transmembrane segment contributes to agonist efficacy differences between alpha1 and alpha3 glycine receptors
Formatted title
The M4 transmembrane segment contributes to agonist efficacy differences between α1 and α3 glycine receptors
Journal name Molecular Membrane Biology   Check publisher's open access policy
ISSN 0968-7688
1464-5203
Publication date 2009-07-20
Year available 2009
Sub-type Article (original research)
DOI 10.1080/09687680903120319
Volume 26
Issue 5-7
Start page 321
End page 332
Total pages 12
Place of publication London, England, United Kingdom
Publisher Informa Healthcare
Collection year 2010
Language eng
Subject C1
110903 Central Nervous System
920111 Nervous System and Disorders
Abstract To date there are few compounds known to pharmacologically discriminate between 1 and 3 subunit-containing glycine receptors (GlyRs). The present study stemmed from an observation that the glycinergic agonists, taurine and -alanine, act with much lower agonist efficacy at 3 GlyRs than at 1 GlyRs. We sought to understand the structural basis of this difference to provide insights relevant to the development of 3-specific modulators as leads for the development of new anti-inflammatory analgesics. Using chimeras of 1 and 3 subunits, we identified the structurally divergent M4 transmembrane segment and C-terminal tail as a specific determinant of the efficacy difference. Because mutation of individual non-conserved M4 residues had little influence on agonist efficacies, the reduced agonist efficacy at 3 GlyRs is most likely a distributed effect of all non-conserved M4 residues. Given the lack of contact between M4 and other transmembrane segments, the efficacy differences are probably mediated by differential interactions with the surrounding lipid environment. This may explain why GlyR agonist efficacies differ among expression systems where membrane lipid composition is not conserved. It may also explain why GlyR agonist efficacy increases at high expression densities, as this would increase the propensity of receptors to cluster thereby inducing M4 segments of neighboring receptors to interact. This strong influence of M4 primary structure on partial agonist efficacy suggests that the relatively poorly conserved 3 GlyR M4 segment may be a promising domain to target in the search for 3 GlyR-specific modulators.
Keyword Cys-loop receptor
Agonist efficacy
Protein-lipid interactions
Taurine-alanine
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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Created: Wed, 20 Jan 2010, 15:29:07 EST by Debra McMurtrie on behalf of School of Biomedical Sciences