ArticleProceedings of the National Academy of Sciences of the United States of America2011
Functional prokaryotic-eukaryotic chimera from the pentameric ligand-gated ion channel family.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 83 citations in OpenAlex.
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- Reconstitution of an N-AChR from Brugia malayi, an evolved change in acetylcholine receptor accessory protein requirements in filarial parasites.PLoS pathogens · 2022Article
- Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway.Science advances · 2022Article
- Probing the molecular basis for signal transduction through the Zinc-Activated Channel (ZAC).Biochemical pharmacology · 2021Article
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- Signal transduction through Cys-loop receptors is mediated by the nonspecific bumping of closely apposed domains.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
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- A chimeric prokaryotic-eukaryotic pentameric ligand gated ion channel reveals interactions between the extracellular and transmembrane domains shape neurosteroid modulation.Neuropharmacology · 2017Article
- String method solution of the gating pathways for a pentameric ligand-gated ion channel.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
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- Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors.Molecular pharmacology · 2016Review
- Potentiators exert distinct effects on human, murine, and Xenopus CFTR.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- Functional characterization of neurotransmitter activation and modulation in a nematode model ligand-gated ion channel.Journal of neurochemistry · 2016Article
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- Ethanol effects on glycinergic transmission: From molecular pharmacology to behavior responses.Pharmacological research · 2015Review
- The M4 Transmembrane α-Helix Contributes Differently to Both the Maturation and Function of Two Prokaryotic Pentameric Ligand-gated Ion Channels.The Journal of biological chemistry · 2015Article
- A chimeric prokaryotic pentameric ligand-gated channel reveals distinct pathways of activation.The Journal of general physiology · 2015Article
- Role of the Fourth Transmembrane α Helix in the Allosteric Modulation of Pentameric Ligand-Gated Ion Channels.Structure (London, England : 1993) · 2015Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pentameric ligand-gated ion channels (pLGICs), which mediate chemo-electric signal transduction in animals, have been recently found in bacteria. Despite clear sequence and 3D structure homology, the phylogenetic distance between prokaryotic and eukaryotic homologs suggests significant structural divergences, especially at the interface between the extracellular (ECD) and the transmembrane (TMD) domains. To challenge this possibility, we constructed a chimera in which the ECD of the bacterial protein GLIC is fused to the TMD of the human α1 glycine receptor (α1GlyR). Electrophysiology in Xenopus oocytes shows that it functions as a proton-gated ion channel, thereby locating the proton activation site(s) of GLIC in its ECD. Patch-clamp experiments in BHK cells show that the ion channel displays an anionic selectivity with a unitary conductance identical to that of the α1GlyR. In addition, pharmacological investigations result in transmembrane allosteric modulation similar to the one observed on α1GlyR. Indeed, the clinically active drugs propofol, four volatile general anesthetics, alcohols, and ivermectin all potentiate the chimera while they inhibit GLIC. Collectively, this work shows the compatibility between GLIC and α1GlyR domains and points to conservation of the ion channel and transmembrane allosteric regulatory sites in the chimera. This provides evidence that GLIC and α1GlyR share a highly homologous 3D structure. GLIC is thus a relevant model of eukaryotic pLGICs, at least from the anionic type. In addition, the chimera is a good candidate for mass production in Escherichia coli, opening the way for investigations of "druggable" eukaryotic allosteric sites by X-ray crystallography.
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