Change search
ReferencesLink to record
Permanent link

Direct link
Molecular mechanism for the dual alcohol modulation of cys loop receptors
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Show others and affiliations
2012 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 8, no 10, e1002710- p.Article in journal (Refereed) Published
Abstract [en]

Cys-loop receptors constitute a superfamily of pentameric ligand-gated ion channels (pLGICs), including receptors for acetylcholine, serotonin, glycine and gamma-aminobutyric acid. Several bacterial homologues have been identified that are excellent models for understanding allosteric binding of alcohols and anesthetics in human Cys-loop receptors. Recently, we showed that a single point mutation on a prokaryotic homologue (GLIC) could transform it from a channel weakly potentiated by ethanol into a highly ethanol-sensitive channel. Here, we have employed molecular simulations to study ethanol binding to GLIC, and to elucidate the role of the ethanol-enhancing mutation in GLIC modulation. By performing 1-mu s simulations with and without ethanol on wild-type and mutated GLIC, we observed spontaneous binding in both intra-subunit and inter-subunit transmembrane cavities. In contrast to the glycine receptor GlyR, in which we previously observed ethanol binding primarily in an inter-subunit cavity, ethanol primarily occupied an intra-subunit cavity in wild-type GLIC. However, the highly ethanol-sensitive GLIC mutation significantly enhanced ethanol binding in the inter-subunit cavity. These results demonstrate dramatic effects of the F(14')A mutation on the distribution of ligands, and are consistent with a two-site model of pLGIC inhibition and potentiation.

Place, publisher, year, edition, pages
2012. Vol. 8, no 10, e1002710- p.
National Category
Biochemistry and Molecular Biology Bioinformatics (Computational Biology)
URN: urn:nbn:se:su:diva-83992DOI: 10.1371/journal.pcbi.1002710ISI: 000310568800011OAI: diva2:577951


Available from: 2012-12-17 Created: 2012-12-17 Last updated: 2012-12-17Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Lindahl, Erik
By organisation
Department of Biochemistry and Biophysics
In the same journal
PloS Computational Biology
Biochemistry and Molecular BiologyBioinformatics (Computational Biology)

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 27 hits
ReferencesLink to record
Permanent link

Direct link