ArticleThe Journal of biological chemistry2009
Loop 2 structure in glycine and GABA(A) receptors plays a key role in determining ethanol sensitivity.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 35 citations in OpenAlex.
- A newly developed anesthetic based on a unique chemical core.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Permeating disciplines: Overcoming barriers between molecular simulations and classical structure-function approaches in biological ion transport.Biochimica et biophysica acta. Biomembranes · 2018Review
- Trapping of ivermectin by a pentameric ligand-gated ion channel upon open-to-closed isomerization.Scientific reports · 2017Article
- Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC.Structure (London, England : 1993) · 2017Article
- Mutational Analysis at Intersubunit Interfaces of an Anionic Glutamate Receptor Reveals a Key Interaction Important for Channel Gating by Ivermectin.Frontiers in molecular neuroscience · 2017Article
- Subunit stoichiometry and arrangement in a heteromeric glutamate-gated chloride channel.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Potentiation of Gamma Aminobutyric Acid Receptors (GABAAR) by Ethanol: How Are Inhibitory Receptors Affected?Frontiers in cellular neuroscience · 2016Review
- Article
- Ethanol Modulation is Quantitatively Determined by the Transmembrane Domain of Human α1 Glycine Receptors.Alcoholism, clinical and experimental research · 2015Article
- Control of ethanol sensitivity of the glycine receptor α3 subunit by transmembrane 2, the intracellular splice cassette and C-terminal domains.The Journal of pharmacology and experimental therapeutics · 2015Article
- Evidence for α-helices in the large intracellular domain mediating modulation of the α1-glycine receptor by ethanol and Gβγ.The Journal of pharmacology and experimental therapeutics · 2015Article
- Glycine and GABA(A) ultra-sensitive ethanol receptors as novel tools for alcohol and brain research.Molecular pharmacology · 2014Article
- Altered sedative effects of ethanol in mice with α1 glycine receptor subunits that are insensitive to Gβγ modulation.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2014Article
- International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands.Pharmacological reviews · 2014Article
- Structural models of ligand-gated ion channels: sites of action for anesthetics and ethanol.Alcoholism, clinical and experimental research · 2014Review
- Seeking structural specificity: direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics.Pharmacological reviews · 2014Review
- Zinc-dependent modulation of α2- and α3-glycine receptor subunits by ethanol.Alcoholism, clinical and experimental research · 2013Article
- Tryptophan 46 is a site for ethanol and ivermectin action in P2X4 receptors.Purinergic signalling · 2013Article
- Intermediate closed state for glycine receptor function revealed by cysteine cross-linking.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Mutation of a zinc-binding residue in the glycine receptor α1 subunit changes ethanol sensitivity in vitro and alcohol consumption in vivo.The Journal of pharmacology and experimental therapeutics · 2013Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The present study tests the hypothesis that the structure of extracellular domain Loop 2 can markedly affect ethanol sensitivity in glycine receptors (GlyRs) and gamma-aminobutyric acid type A receptors (GABA(A)Rs). To test this, we mutated Loop 2 in the alpha1 subunit of GlyRs and in the gamma subunit of alpha1beta2gamma2GABA(A)Rs and measured the sensitivity of wild type and mutant receptors expressed in Xenopus oocytes to agonist, ethanol, and other agents using two-electrode voltage clamp. Replacing Loop 2 of alpha1GlyR subunits with Loop 2 from the deltaGABA(A)R (deltaL2), but not the gammaGABA(A)R subunit, reduced ethanol threshold and increased the degree of ethanol potentiation without altering general receptor function. Similarly, replacing Loop 2 of the gamma subunit of GABA(A)Rs with deltaL2 shifted the ethanol threshold from 50 mm in WT to 1 mm in the GABA(A) gamma-deltaL2 mutant. These findings indicate that the structure of Loop 2 can profoundly affect ethanol sensitivity in GlyRs and GABA(A)Rs. The deltaL2 mutations did not affect GlyR or GABA(A)R sensitivity, respectively, to Zn(2+) or diazepam, which suggests that these deltaL2-induced changes in ethanol sensitivity do not extend to all allosteric modulators and may be specific for ethanol or ethanol-like agents. To explore molecular mechanisms underlying these results, we threaded the WT and deltaL2 GlyR sequences onto the x-ray structure of the bacterial Gloeobacter violaceus pentameric ligand-gated ion channel homologue (GLIC). In addition to being the first GlyR model threaded on GLIC, the juxtaposition of the two structures led to a possible mechanistic explanation for the effects of ethanol on GlyR-based on changes in Loop 2 structure.
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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.