ArticleThe Journal of pharmacology and experimental therapeutics2013
Mutation of a zinc-binding residue in the glycine receptor α1 subunit changes ethanol sensitivity in vitro and alcohol consumption in vivo.
Article in The Journal of pharmacology and experimental therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 26 citations in OpenAlex.
- An emerging role for synaptic ZnPharmacology & therapeutics · 2026Review
- Methods for negating the impact of zinc contamination to allow characterization of positive allosteric modulators of glycine receptors.Frontiers in molecular neuroscience · 2024Article
- Positive Allosteric Modulators of Glycine Receptors and Their Potential Use in Pain Therapies.Pharmacological reviews · 2022Review
- The Function and Regulation of Zinc in the Brain.Neuroscience · 2021Review
- SNARE Complex-Associated Proteins and Alcohol.Alcoholism, clinical and experimental research · 2020Review
- Zinc deficiency as a mediator of toxic effects of alcohol abuse.European journal of nutrition · 2018Review
- Titrating Tipsy Targets: The Neurobiology of Low-Dose Alcohol.Trends in pharmacological sciences · 2017Review
- Interactions between Zinc and Allosteric Modulators of the Glycine Receptor.The Journal of pharmacology and experimental therapeutics · 2017Article
- Reversal of Ethanol-induced Intoxication by a Novel Modulator of Gβγ Protein Potentiation of the Glycine Receptor.The Journal of biological chemistry · 2016Article
- Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors.Molecular pharmacology · 2016Review
- Defects of the Glycinergic Synapse in Zebrafish.Frontiers in molecular neuroscience · 2016Review
- Glycine receptors containing α2 or α3 subunits regulate specific ethanol-mediated behaviors.The Journal of pharmacology and experimental therapeutics · 2015Article
- Investigational therapies for the pharmacological treatment of alcoholism.Expert opinion on investigational drugs · 2015Article
- Extrasynaptic glycine receptors of rodent dorsal raphe serotonergic neurons: a sensitive target for ethanol.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2014Article
- Proteomic approaches and identification of novel therapeutic targets for alcoholism.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2014Review
- Zinc-dependent modulation of α2- and α3-glycine receptor subunits by ethanol.Alcoholism, clinical and experimental research · 2013Article
- Glycine receptor mouse mutants: model systems for human hyperekplexia.British journal of pharmacology · 2013Review
- Positively correlated miRNA-mRNA regulatory networks in mouse frontal cortex during early stages of alcohol dependence.BMC genomics · 2013Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Ethanol is a widely used drug, yet an understanding of its sites and mechanisms of action remains incomplete. Among the protein targets of ethanol are glycine receptors (GlyRs), which are potentiated by millimolar concentrations of ethanol. In addition, zinc ions also modulate GlyR function, and recent evidence suggests that physiologic concentrations of zinc enhance ethanol potentiation of GlyRs. Here, we first built a homology model of a zinc-bound GlyR using the D80 position as a coordination site for a zinc ion. Next, we investigated in vitro the effects of zinc on ethanol action at recombinant wild-type (WT) and mutant α1 GlyRs containing the D80A substitution, which eliminates zinc potentiation. At D80A GlyRs, the effects of 50 and 200 mM ethanol were reduced as compared with WT receptors. Also, in contrast to what was seen with WT GlyRs, neither adding nor chelating zinc changed the magnitude of ethanol enhancement of mutant D80A receptors. Next, we evaluated the in vivo effects of the D80A substitution by using heterozygous Glra1(D80A) knock-in (KI) mice. The KI mice showed decreased ethanol consumption and preference, and they displayed increased startle responses compared with their WT littermates. Other behavioral tests, including ethanol-induced motor incoordination and strychnine-induced convulsions, revealed no differences between the KI and WT mice. Together, our findings indicate that zinc is critical in determining the effects of ethanol at GlyRs and suggest that zinc binding at the D80 position may be important for mediating some of the behavioral effects of ethanol action at GlyRs.
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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.