Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
The present studies used increased atmospheric pressure in place of a traditional pharmacological antagonist to probe the molecular sites and mechanisms of ethanol action in glycine receptors (GlyRs). Based on previous studies, we tested the hypothesis that physical-chemical properties at position 52 in extracellular domain Loop 2 of alpha1GlyRs, or the homologous alpha2GlyR position 59, determine sensitivity to ethanol and pressure antagonism of ethanol. Pressure antagonized ethanol in alpha1GlyRs that contain a non-polar residue at position 52, but did not antagonize ethanol in receptors with a polar residue at this position. Ethanol sensitivity in receptors with polar substitutions at position 52 was significantly lower than GlyRs with non-polar residues at this position. The alpha2T59A mutation switched sensitivity to ethanol and pressure antagonism in the WTalpha2GlyR, thereby making it alpha1-like. Collectively, these findings indicate that (i) polarity at position 52 plays a key role in determining sensitivity to ethanol and pressure antagonism of ethanol; (ii) the extracellular domain in alpha1- and alpha2GlyRs is a target for ethanol action and antagonism and (iii) there is structural-functional homology across subunits in Loop 2 of GlyRs with respect to their roles in determining sensitivity to ethanol and pressure antagonism of ethanol. These findings should help in the development of pharmacological agents that antagonize ethanol.
Aguayo,
Ethanol modulation of the gamma-aminobutyric acidA- and glycine-activated Cl- current in cultured mouse neurons.
1994, Pubmed
Aguayo,
Ethanol modulation of the gamma-aminobutyric acidA- and glycine-activated Cl- current in cultured mouse neurons.
1994,
Pubmed Alkana,
Low-level hyperbaric ethanol antagonism in mice. Dose and pressure response.
1981,
Pubmed Alkana,
Low-level hyperbaric exposure antagonizes locomotor effects of ethanol and n-propanol but not morphine in C57BL mice.
1995,
Pubmed Alkana,
Hyperbaric ethanol antagonism in mice: studies on oxygen, nitrogen, strain and sex.
1982,
Pubmed Alkana,
The effects of low level hyperbaric treatment on acute ethanol intoxication.
1980,
Pubmed Bejanian,
Low-level hyperbaric antagonism of ethanol-induced locomotor depression in C57BL/6J mice: dose response.
1993,
Pubmed Betz,
Glycine receptors: heterogeneous and widespread in the mammalian brain.
1991,
Pubmed Bowser-Riley,
Investigations into the origin of the high pressure neurological syndrome: the interaction between pressure, strychnine and 1,2-propandiols in the mouse.
1988,
Pubmed Cardoso,
Effects of ethanol on recombinant human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes.
1999,
Pubmed
,
Xenbase Colombo,
The cannabinoid CB1 receptor antagonist, rimonabant, as a promising pharmacotherapy for alcohol dependence: preclinical evidence.
2007,
Pubmed Crawford,
Evidence that ethanol acts on a target in Loop 2 of the extracellular domain of alpha1 glycine receptors.
2007,
Pubmed
,
Xenbase Davies,
Direct antagonism of ethanol's effects on GABA(A) receptors by increased atmospheric pressure.
1998,
Pubmed Davies,
Low level hyperbaric antagonism of diazepam's locomotor depressant and anticonvulsant properties in mice.
1996,
Pubmed Davies,
Multiple sites of ethanol action in alpha1 and alpha2 glycine receptors suggested by sensitivity to pressure antagonism.
2004,
Pubmed
,
Xenbase Davies,
Low-level hyperbaric antagonism of ethanol's anticonvulsant property in C57BL/6J mice.
1994,
Pubmed Davies,
Ethanol enhances GABAA receptor function in short sleep and long sleep mouse brain membranes.
2001,
Pubmed Davies,
Ethanol potentiation of glycine receptors expressed in Xenopus oocytes antagonized by increased atmospheric pressure.
2003,
Pubmed
,
Xenbase Davies,
In vivo and in vitro hyperbaric studies in mice suggest novel sites of action for ethanol.
1999,
Pubmed Deitrich,
Mechanism of action of ethanol: initial central nervous system actions.
1989,
Pubmed Dougherty,
Cation-pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp.
1996,
Pubmed Dunn,
Mutagenesis of the rat alpha1 subunit of the gamma-aminobutyric acid(A) receptor reveals the importance of residue 101 in determining the allosteric effects of benzodiazepine site ligands.
1999,
Pubmed
,
Xenbase Eckenhoff,
Molecular interactions between inhaled anesthetics and proteins.
1997,
Pubmed Eggers,
Developmental changes in the modulation of synaptic glycine receptors by ethanol.
2000,
Pubmed Eisenberg,
The hydrophobic moment detects periodicity in protein hydrophobicity.
1984,
Pubmed Engblom,
Effect of ethanol on gamma-aminobutyric acid and glycine receptor-coupled Cl- fluxes in rat brain synaptoneurosomes.
1991,
Pubmed Franks,
Inhibitory synapses. Anaesthetics set their sites on ion channels.
1997,
Pubmed Franks,
Molecular and cellular mechanisms of general anaesthesia.
1994,
Pubmed Grant,
The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991-1992 and 2001-2002.
2004,
Pubmed Harris,
Ethanol actions on multiple ion channels: which are important?
1999,
Pubmed Heilig,
Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms.
2006,
Pubmed Imai,
Theoretical study of volume changes accompanying xenon-lysozyme binding: implications for the molecular mechanism of pressure reversal of anesthesia.
2006,
Pubmed Johnson,
Topiramate for treating alcohol dependence: a randomized controlled trial.
2007,
Pubmed Karlin,
Emerging structure of the nicotinic acetylcholine receptors.
2002,
Pubmed Karlin,
Substituted-cysteine accessibility method.
1998,
Pubmed Little,
How has molecular pharmacology contributed to our understanding of the mechanism(s) of general anesthesia?
1996,
Pubmed Lobo,
Cross-linking of sites involved with alcohol action between transmembrane segments 1 and 3 of the glycine receptor following activation.
2008,
Pubmed
,
Xenbase Malashkevich,
The crystal structure of a five-stranded coiled coil in COMP: a prototype ion channel?
1996,
Pubmed Malosio,
Widespread expression of glycine receptor subunit mRNAs in the adult and developing rat brain.
1991,
Pubmed Mascia,
A single amino acid determines differences in ethanol actions on strychnine-sensitive glycine receptors.
1996,
Pubmed
,
Xenbase Mascia,
Specific binding sites for alcohols and anesthetics on ligand-gated ion channels.
2000,
Pubmed
,
Xenbase Mascia,
Enhancement of homomeric glycine receptor function by long-chain alcohols and anaesthetics.
1996,
Pubmed
,
Xenbase Mastrangelo,
Nerve membrane lipid fluidity: opposing effects of high pressure and ethanol.
1979,
Pubmed McCool,
Effects of chronic ethanol consumption on rat GABA(A) and strychnine-sensitive glycine receptors expressed by lateral/basolateral amygdala neurons.
2003,
Pubmed Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase Miller,
The pressure reversal of general anesthesia and the critical volume hypothesis.
1973,
Pubmed Molander,
Accumbal strychnine-sensitive glycine receptors: an access point for ethanol to the brain reward system.
2005,
Pubmed Molander,
The glycine reuptake inhibitor Org 25935 decreases ethanol intake and preference in male wistar rats.
2007,
Pubmed Mori,
Membrane expansion and inhalation anesthetics. Mean excess volume hypothesis.
1984,
Pubmed Ortells,
Evolutionary history of the ligand-gated ion-channel superfamily of receptors.
1995,
Pubmed Quillin,
Size versus polarizability in protein-ligand interactions: binding of noble gases within engineered cavities in phage T4 lysozyme.
2000,
Pubmed Rajendra,
The glycine receptor.
1997,
Pubmed Ryan,
A missense mutation in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor in the spasmodic mouse.
1994,
Pubmed Saul,
Point mutation of glycine receptor alpha 1 subunit in the spasmodic mouse affects agonist responses.
1994,
Pubmed
,
Xenbase Schofield,
Sequence and functional expression of the GABA A receptor shows a ligand-gated receptor super-family.
,
Pubmed
,
Xenbase Steensland,
Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking.
2007,
Pubmed Syapin,
Antagonism of ethanol-induced depression of mouse locomotor activity by hyperbaric exposure.
1988,
Pubmed Tao,
Protein kinase C modulation of ethanol inhibition of glycine-activated current in dissociated neurons of rat ventral tegmental area.
2002,
Pubmed Tapia,
Ethanol affects the function of a neurotransmitter receptor protein without altering the membrane lipid phase.
1998,
Pubmed Trudell,
Pressure-induced elevation of phase transition temperature in dipalmitoylphosphatidylcholine bilayers. An electron spin resonance measurement of the enthalpy of phase transition.
1974,
Pubmed Trudell,
Pressure reversal of inhalation anesthetic-induced disorder in spin-labeled phospholipid vesicles.
1973,
Pubmed Valenzuela,
Effects of ethanol on recombinant glycine receptors expressed in mammalian cell lines.
1998,
Pubmed
,
Xenbase Wallner,
Low-dose alcohol actions on alpha4beta3delta GABAA receptors are reversed by the behavioral alcohol antagonist Ro15-4513.
2006,
Pubmed
,
Xenbase Wann,
Actions and interactions of high pressure and general anaesthetics.
1988,
Pubmed Weber,
The effect of high pressure upon proteins and other biomolecules.
1983,
Pubmed Wick,
Mutations of gamma-aminobutyric acid and glycine receptors change alcohol cutoff: evidence for an alcohol receptor?
1998,
Pubmed
,
Xenbase Ye,
Decay of ethanol-induced suppression of glycine-activated current of ventral tegmental area neurons.
2002,
Pubmed Ye,
Enhancement of glycine receptor function by ethanol is inversely correlated with molecular volume at position alpha267.
1998,
Pubmed
,
Xenbase Yevenes,
Molecular determinants for G protein betagamma modulation of ionotropic glycine receptors.
2006,
Pubmed Zhou,
Pharmacologic characteristics of potentiation of 5-HT3 receptors by alcohols and diethyl ether in NCB-20 neuroblastoma cells.
1996,
Pubmed Zimmerman,
The characterization of amino acid sequences in proteins by statistical methods.
1968,
Pubmed Ziskind-Conhaim,
Ethanol dual modulatory actions on spontaneous postsynaptic currents in spinal motoneurons.
2003,
Pubmed
