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- Title
Molecular Mechanism for the Dual Alcohol Modulation of Cys-loop Receptors.
- Authors
Murail, Samuel; Howard, Rebecca J.; Broemstrup, Torben; Bertaccini, Edward J.; Harris, R. Adron; Trudell, James R.; Lindahl, Erik
- Abstract
Cys-loop receptors constitute a superfamily of pentameric ligand-gated ion channels (pLGICs), including receptors for acetylcholine, serotonin, glycine and c-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- ms simulations with and without ethanol on wild-type and mutated GLIC, we observed spontaneous binding in both intrasubunit 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.
- Subjects
ION channels; CHOLINERGIC receptors; GENETIC mutation; GLYCINE receptors; ETHANOL
- Publication
PLoS Computational Biology, 2012, Vol 8, Issue 10, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1002710