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Alcohol Clin Exp Res
2015 Jun 01;396:962-8. doi: 10.1111/acer.12735.
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Ethanol Modulation is Quantitatively Determined by the Transmembrane Domain of Human α1 Glycine Receptors.
Horani S
,
Stater EP
,
Corringer PJ
,
Trudell JR
,
Harris RA
,
Howard RJ
.
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Mutagenesis and labeling studies have identified amino acids from the human α1 glycine receptor (GlyR) extracellular, transmembrane (TM), and intracellular domains in mediating ethanol (EtOH) potentiation. However, limited high-resolution structural data for physiologically relevant receptors in this Cys-loop receptor superfamily have made pinpointing the critical amino acids difficult. Homologous ion channels from lower organisms provide conserved models for structural and functional properties of Cys-loop receptors. We previously demonstrated that a single amino acid variant of the Gloeobacter violaceus ligand-gated ion channel (GLIC) produced EtOH and anesthetic sensitivity similar to that of GlyRs and provided crystallographic evidence for EtOH binding to GLIC. We directly compared EtOH modulation of the α1 GlyR and GLIC to a chimera containing the TM domain from human α1 GlyRs and the ligand-binding domain of GLIC using 2-electrode voltage-clamp electrophysiology of receptors expressed in Xenopus laevis oocytes. EtOH potentiated α1 GlyRs in a concentration-dependent manner in the presence of zinc-chelating agents, but did not potentiate GLIC at pharmacologically relevant concentrations. The GLIC/GlyR chimera recapitulated the EtOH potentiation of GlyRs, without apparent sensitivity to zinc chelation. For chimera expression in oocytes, it was essential to suppress leakage current by adding 50 μM picrotoxin to the media, a technique that may have applications in expression of other ion channels. Our results are consistent with a TM mechanism of EtOH modulation in Cys-loop receptors. This work highlights the relevance of bacterial homologs as valuable model systems for studying ion channel function of human receptors and demonstrates the modularity of these channels across species.
Alqazzaz,
Cys-loop receptor channel blockers also block GLIC.
2011, Pubmed
Alqazzaz,
Cys-loop receptor channel blockers also block GLIC.
2011,
Pubmed
Bocquet,
X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation.
2009,
Pubmed
Borghese,
Characterization of two mutations, M287L and Q266I, in the α1 glycine receptor subunit that modify sensitivity to alcohols.
2012,
Pubmed
,
Xenbase
Chen,
Molecular determinants of proton modulation of glycine receptors.
2004,
Pubmed
Chiara,
Photoaffinity labeling the propofol binding site in GLIC.
2014,
Pubmed
,
Xenbase
Duret,
Functional prokaryotic-eukaryotic chimera from the pentameric ligand-gated ion channel family.
2011,
Pubmed
,
Xenbase
Forman,
Monod-Wyman-Changeux allosteric mechanisms of action and the pharmacology of etomidate.
2012,
Pubmed
Hassaine,
X-ray structure of the mouse serotonin 5-HT3 receptor.
2014,
Pubmed
Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed
Hilf,
Structural basis of open channel block in a prokaryotic pentameric ligand-gated ion channel.
2010,
Pubmed
,
Xenbase
Hilf,
Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel.
2009,
Pubmed
Howard,
Structural basis for alcohol modulation of a pentameric ligand-gated ion channel.
2011,
Pubmed
,
Xenbase
Hu,
Mutations of L293 in transmembrane two of the mouse 5-hydroxytryptamine3A receptor alter gating and alcohol modulatory actions.
2006,
Pubmed
,
Xenbase
Jayakar,
Identification of propofol binding sites in a nicotinic acetylcholine receptor with a photoreactive propofol analog.
2013,
Pubmed
Jayakar,
Multiple propofol-binding sites in a γ-aminobutyric acid type A receptor (GABAAR) identified using a photoreactive propofol analog.
2014,
Pubmed
Lidö,
The glycine reuptake inhibitor org 25935 interacts with basal and ethanol-induced dopamine release in rat nucleus accumbens.
2009,
Pubmed
Mascia,
Specific binding sites for alcohols and anesthetics on ligand-gated ion channels.
2000,
Pubmed
,
Xenbase
Mascia,
A single amino acid determines differences in ethanol actions on strychnine-sensitive glycine receptors.
1996,
Pubmed
,
Xenbase
McCracken,
Zinc enhances ethanol modulation of the alpha1 glycine receptor.
2010,
Pubmed
,
Xenbase
Miller,
Crystal structure of a human GABAA receptor.
2014,
Pubmed
Miller,
Molecular basis for zinc potentiation at strychnine-sensitive glycine receptors.
2005,
Pubmed
Moraga-Cid,
Allosteric and hyperekplexic mutant phenotypes investigated on an α1 glycine receptor transmembrane structure.
2015,
Pubmed
Mowrey,
Open-channel structures of the human glycine receptor α1 full-length transmembrane domain.
2013,
Pubmed
Naito,
Glycine and GABA(A) ultra-sensitive ethanol receptors as novel tools for alcohol and brain research.
2014,
Pubmed
,
Xenbase
Nury,
X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel.
2011,
Pubmed
Nys,
Structural insights into Cys-loop receptor function and ligand recognition.
2013,
Pubmed
Olsen,
Structural models of ligand-gated ion channels: sites of action for anesthetics and ethanol.
2014,
Pubmed
Pan,
Structure of the pentameric ligand-gated ion channel GLIC bound with anesthetic ketamine.
2012,
Pubmed
,
Xenbase
Paoletti,
Zinc at glutamatergic synapses.
2009,
Pubmed
Perkins,
Loop 2 structure in glycine and GABA(A) receptors plays a key role in determining ethanol sensitivity.
2009,
Pubmed
,
Xenbase
Perkins,
Charge and geometry of residues in the loop 2 β hairpin differentially affect agonist and ethanol sensitivity in glycine receptors.
2012,
Pubmed
,
Xenbase
Perkins,
Molecular targets and mechanisms for ethanol action in glycine receptors.
2010,
Pubmed
Pettersen,
UCSF Chimera--a visualization system for exploratory research and analysis.
2004,
Pubmed
Prevost,
A locally closed conformation of a bacterial pentameric proton-gated ion channel.
2012,
Pubmed
Rienzo,
Structural requirements in the transmembrane domain of GLIC revealed by incorporation of noncanonical histidine analogs.
2014,
Pubmed
,
Xenbase
Sánchez,
Control of ethanol sensitivity of the glycine receptor α3 subunit by transmembrane 2, the intracellular splice cassette and C-terminal domains.
2015,
Pubmed
Sauguet,
Crystal structures of a pentameric ligand-gated ion channel provide a mechanism for activation.
2014,
Pubmed
,
Xenbase
Sauguet,
Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel.
2013,
Pubmed
Schoberth,
Ethanol transport in Zymomonas mobilis measured by using in vivo nuclear magnetic resonance spin transfer.
1996,
Pubmed
Scott,
Correlating structural and energetic changes in glycine receptor activation.
2015,
Pubmed
Söderpalm,
Neurocircuitry involved in the development of alcohol addiction: the dopamine system and its access points.
2013,
Pubmed
Spurny,
Multisite binding of a general anesthetic to the prokaryotic pentameric Erwinia chrysanthemi ligand-gated ion channel (ELIC).
2013,
Pubmed
,
Xenbase
Talwar,
Phosphorylation mediated structural and functional changes in pentameric ligand-gated ion channels: implications for drug discovery.
2014,
Pubmed
Wang,
Intramembrane proton binding site linked to activation of bacterial pentameric ion channel.
2012,
Pubmed
Weng,
Anesthetic sensitivity of the Gloeobacter violaceus proton-gated ion channel.
2010,
Pubmed
,
Xenbase
Yang,
A proposed structural basis for picrotoxinin and picrotin binding in the glycine receptor pore.
2007,
Pubmed
Yevenes,
A selective G betagamma-linked intracellular mechanism for modulation of a ligand-gated ion channel by ethanol.
2008,
Pubmed
