ArticleStructure (London, England : 1993)2013
Inhibition versus potentiation of ligand-gated ion channels can be altered by a single mutation that moves ligands between intra- and intersubunit sites.
Article in Structure (London, England : 1993), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- General anesthetic modulation of a pentameric ligand-gated ion channel explored with simulations.Biophysical journal · 2026Article
- Discovery of an allosteric binding site for anthraquinones at the human P2X4 receptor.Nature communications · 2025Article
- Haloperidol, a typical antipsychotic, inhibits 5-HTThe Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2025Article
- Mutagenesis computer experiments in pentameric ligand-gated ion channels: the role of simulation tools with different resolution.Interface focus · 2019Review
- GABANeuropharmacology · 2018Review
- Permeating disciplines: Overcoming barriers between molecular simulations and classical structure-function approaches in biological ion transport.Biochimica et biophysica acta. Biomembranes · 2018Review
- Ketamine Inhibition of the Pentameric Ligand-Gated Ion Channel GLIC.Biophysical journal · 2017Article
- A membrane-embedded pathway delivers general anesthetics to two interacting binding sites in theThe Journal of biological chemistry · 2017Article
- Functional characterization of neurotransmitter activation and modulation in a nematode model ligand-gated ion channel.Journal of neurochemistry · 2016Article
- Identification of an Inhibitory Alcohol Binding Site in GABAA ρ1 Receptors.ACS chemical neuroscience · 2016Article
- The molecular pharmacology of volatile anesthetics.International anesthesiology clinics · 2015Review
- Hydrocarbon molar water solubility predicts NMDA vs. GABAA receptor modulation.BMC pharmacology & toxicology · 2014Article
- Atomistic models of general anesthetics for use in in silico biological studies.The journal of physical chemistry. B · 2014Article
- Modulation of a voltage-gated Na+ channel by sevoflurane involves multiple sites and distinct mechanisms.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Pentameric Ligand-gated Ion Channels : Insights from Computation.Molecular simulation · 2014Article
- Seeking structural specificity: direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics.Pharmacological reviews · 2014Review
Corrections and comments
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Authors and funding
5 authors at 4 institutions in 2 countries.
Funding
Abstract
Pentameric ligand-gated ion channels (pLGICs) are similar in structure but either inhibited or potentiated by alcohols and anesthetics. This dual modulation has previously not been understood, but the determination of X-ray structures of prokaryotic GLIC provides an ideal model system. Here, we show that a single-site mutation at the F14' site in the GLIC transmembrane domain turns desflurane and chloroform from inhibitors to potentiators, and that this is explained by competing allosteric sites. The F14'A mutation opens an intersubunit site lined by N239 (15'), I240 (16'), and Y263. Free energy calculations confirm this site is the preferred binding location for desflurane and chloroform in GLIC F14'A. In contrast, both anesthetics prefer an intrasubunit site in wild-type GLIC. Modulation is therefore the net effect of competitive binding between the intersubunit potentiating site and an intrasubunit inhibitory site. This provides direct evidence for a dual-site model of allosteric regulation of pLGICs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.