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Evidence that ethanol acts on a target in Loop 2 of the extracellular domain of alpha1 glycine receptors.
Evidence that ethanol acts on a target in Loop 2 of the extracellular domain of alpha1 glycine receptors.
- Source :
-
Journal of neurochemistry [J Neurochem] 2007 Sep; Vol. 102 (6), pp. 2097-2109. Date of Electronic Publication: 2007 Jun 11. - Publication Year :
- 2007
-
Abstract
- Considerable evidence indicates that ethanol acts on specific residues in the transmembrane domains of glycine receptors (GlyRs). In this study, we tested the hypothesis that the extracellular domain is also a target for ethanol action by investigating the effect of cysteine substitutions at positions 52 (extracellular domain) and 267 (transmembrane domain) on responses to n-alcohols and propyl methanethiosulfonate (PMTS) in alpha1GlyRs expressed in Xenopus oocytes. In support of the hypothesis: (i) The A52C mutation changed ethanol sensitivity compared to WT GlyRs; (ii) PMTS produced irreversible alcohol-like potentiation in A52C GlyRs; and (iii) PMTS binding reduced the n-chain alcohol cutoff in A52C GlyRs. Further studies used PMTS binding to cysteines at positions 52 or 267 to block ethanol action at one site in order to determine its effect at other site(s). In these situations, ethanol caused negative modulation when acting at position 52 and positive modulation when acting at position 267. Collectively, these findings parallel the evidence that established the TM domain as a target for ethanol, suggest that positions 52 and 267 are part of the same alcohol pocket and indicate that the net effect of ethanol on GlyR function reflects the summation of its positive and negative modulatory effects on different targets.
- Subjects :
- Alcohol-Induced Disorders, Nervous System metabolism
Alcohol-Induced Disorders, Nervous System physiopathology
Alcohols pharmacology
Animals
Binding Sites drug effects
Binding Sites physiology
Cell Membrane metabolism
Central Nervous System Depressants pharmacology
Cysteine chemistry
Cysteine metabolism
Drug Synergism
Estrenes pharmacology
Extracellular Fluid drug effects
Extracellular Fluid metabolism
Female
Mutation genetics
Oocytes
Protein Structure, Tertiary drug effects
Protein Structure, Tertiary physiology
Pyridinium Compounds pharmacology
Receptors, Glycine chemistry
Receptors, Glycine metabolism
Xenopus laevis
Cell Membrane drug effects
Ethanol pharmacology
Receptors, Glycine drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3042
- Volume :
- 102
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17561937
- Full Text :
- https://doi.org/10.1111/j.1471-4159.2007.04680.x