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Proc Natl Acad Sci U S A
2000 Aug 01;9716:9305-10. doi: 10.1073/pnas.160128797.
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Specific binding sites for alcohols and anesthetics on ligand-gated ion channels.
Mascia MP
,
Trudell JR
,
Harris RA
.
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Ligand-gated ion channels are a target for inhaled anesthetics and alcohols in the central nervous system. The inhibitory strychnine-sensitive glycine and gamma-aminobutyric acid type A receptors are positively modulated by anesthetics and alcohols, and site-directed mutagenesis techniques have identified amino acid residues important for the action of volatile anesthetics and alcohols in these receptors. A key question is whether these amino acids are part of an alcohol/anesthetic-binding site. In the present study, we used an alkanethiol anesthetic to covalently label its binding site by mutating selected amino acids to cysteine. We demonstrated that the anesthetic propanethiol, or alternatively, propyl methanethiosulfonate, covalently binds to cysteine residues introduced into a specific second transmembrane site in glycine receptor and gamma-aminobutyric acid type A receptor subunits and irreversibly enhances receptor function. Moreover, upon permanent occupation of the site by propyl disulfide, the usual ability of octanol, enflurane, and isoflurane to potentiate the function of the ion channels was lost. This approach provides strong evidence that the actions of anesthetics in these receptors are due to binding at a single site.
Akabas,
Identification of acetylcholine receptor channel-lining residues in the entire M2 segment of the alpha subunit.
1994, Pubmed,
Xenbase
Akabas,
Identification of acetylcholine receptor channel-lining residues in the entire M2 segment of the alpha subunit.
1994,
Pubmed
,
Xenbase
Cantor,
The lateral pressure profile in membranes: a physical mechanism of general anesthesia.
1997,
Pubmed
Dildy-Mayfield,
Actions of long chain alcohols on GABAA and glutamate receptors: relation to in vivo effects.
1996,
Pubmed
,
Xenbase
Downie,
Effects of inhalational general anaesthetics on native glycine receptors in rat medullary neurones and recombinant glycine receptors in Xenopus oocytes.
1996,
Pubmed
,
Xenbase
Eckenhoff,
Molecular interactions between inhaled anesthetics and proteins.
1997,
Pubmed
Forman,
A discrete site for general anesthetics on a postsynaptic receptor.
1995,
Pubmed
,
Xenbase
Franks,
Molecular and cellular mechanisms of general anaesthesia.
1994,
Pubmed
Franks,
Structural basis for the inhibition of firefly luciferase by a general anesthetic.
1998,
Pubmed
Harrison,
Positive modulation of human gamma-aminobutyric acid type A and glycine receptors by the inhalation anesthetic isoflurane.
1993,
Pubmed
Karlin,
Substituted-cysteine accessibility method.
1998,
Pubmed
Kenyon,
Novel sulfhydryl reagents.
1977,
Pubmed
Koltchine,
Agonist gating and isoflurane potentiation in the human gamma-aminobutyric acid type A receptor determined by the volume of a second transmembrane domain residue.
1999,
Pubmed
Lee,
Transmembrane signaling characterized in bacterial chemoreceptors by using sulfhydryl cross-linking in vivo.
1995,
Pubmed
Leite,
Coupled proteolytic and mass spectrometry studies indicate a novel topology for the glycine receptor.
2000,
Pubmed
Lin,
General anesthetics potentiate gamma-aminobutyric acid actions on gamma-aminobutyric acidA receptors expressed by Xenopus oocytes: lack of involvement of intracellular calcium.
1992,
Pubmed
,
Xenbase
Mascia,
Enhancement of homomeric glycine receptor function by long-chain alcohols and anaesthetics.
1996,
Pubmed
,
Xenbase
Mihic,
Potentiation of gamma-aminobutyric acid type A receptor-mediated chloride currents by novel halogenated compounds correlates with their abilities to induce general anesthesia.
1994,
Pubmed
,
Xenbase
Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase
Rajendra,
The glycine receptor.
1997,
Pubmed
Rick,
Neurosteroids act on the GABA(A) receptor at sites on the N-terminal side of the middle of TM2.
1998,
Pubmed
Sankararamakrishnan,
Water-mediated conformational transitions in nicotinic receptor M2 helix bundles: a molecular dynamics study.
1995,
Pubmed
Unwin,
Projection structure of the nicotinic acetylcholine receptor: distinct conformations of the alpha subunits.
1996,
Pubmed
Wick,
Mutations of gamma-aminobutyric acid and glycine receptors change alcohol cutoff: evidence for an alcohol receptor?
1998,
Pubmed
,
Xenbase
Williams,
Gamma-aminobutyric acid increases the water accessibility of M3 membrane-spanning segment residues in gamma-aminobutyric acid type A receptors.
1999,
Pubmed
Yamakura,
Amino acid volume and hydropathy of a transmembrane site determine glycine and anesthetic sensitivity of glycine receptors.
1999,
Pubmed
,
Xenbase
Ye,
Enhancement of glycine receptor function by ethanol is inversely correlated with molecular volume at position alpha267.
1998,
Pubmed
,
Xenbase
Zhang,
The anesthetic potencies of alkanethiols for rats: relevance to theories of narcosis.
2000,
Pubmed