Probing the pharmacological properties of distinct subunit interfaces within heteromeric glycine receptors reveals a functional beta-beta agonist-binding site

Dutertre, Sébastien, Drwal, Malgorzata, Laube, Bodo and Betz, Heinrich (2012) Probing the pharmacological properties of distinct subunit interfaces within heteromeric glycine receptors reveals a functional beta-beta agonist-binding site. Journal of Neurochemistry, 122 1: 38-47. doi:10.1111/j.1471-4159.2012.07755.x


Author Dutertre, Sébastien
Drwal, Malgorzata
Laube, Bodo
Betz, Heinrich
Title Probing the pharmacological properties of distinct subunit interfaces within heteromeric glycine receptors reveals a functional beta-beta agonist-binding site
Formatted title
Probing the pharmacological properties of distinct subunit interfaces within heteromeric glycine receptors reveals a functional ββ agonist-binding site
Journal name Journal of Neurochemistry   Check publisher's open access policy
ISSN 0022-3042
1471-4159
Publication date 2012-07
Sub-type Article (original research)
DOI 10.1111/j.1471-4159.2012.07755.x
Open Access Status DOI
Volume 122
Issue 1
Start page 38
End page 47
Total pages 10
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell Publishing
Subject 1303 Specialist Studies in Education
2804 Cellular and Molecular Neuroscience
Formatted abstract
Synaptic glycine receptors (GlyRs) are hetero-pentameric chloride channels composed of α and β subunits, which are activated by agonist binding at subunit interfaces. To examine the pharmacological properties of each potential agonist-binding site, we substituted residues of the GlyR α1 subunit by the corresponding residues of the β subunit, as deduced from sequence alignment and homology modeling based on the recently published crystal structure of the glutamate-gated chloride channel GluCl. These exchange substitutions allowed us to reproduce the βα, αβ and ββ subunit interfaces present in synaptic heteromeric GlyRs by generating recombinant homomeric receptors. When the engineered α1 GlyR mutants were expressed in Xenopus oocytes, all subunit interface combinations were found to form functional agonist-binding sites as revealed by voltage clamp recording. The ββ-binding site displayed the most distinct pharmacological profile towards a range of agonists and modulators tested, indicating that it might be selectively targeted to modulate the activity of synaptic GlyRs. The mutational approach described here should be generally applicable to heteromeric ligand-gated ion channels composed of homologous subunits and facilitate screening efforts aimed at targeting inter-subunit specific binding sites.
Keyword Agonist binding
GluCl
Glycine receptors
Homology modeling
Ligand-gated ion channel
Site-directed mutagenesis
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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