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Proc Natl Acad Sci U S A
1997 Sep 30;9420:11031-6. doi: 10.1073/pnas.94.20.11031.
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The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid.
Belelli D
,
Lambert JJ
,
Peters JA
,
Wafford K
,
Whiting PJ
.
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The gamma-aminobutyric acid type A (GABAA) receptor is a transmitter-gated ion channel mediating the majority of fast inhibitory synaptic transmission within the brain. The receptor is a pentameric assembly of subunits drawn from multiple classes (alpha1-6, beta1-3, gamma1-3, delta1, and epsilon1). Positive allosteric modulation of GABAA receptor activity by general anesthetics represents one logical mechanism for central nervous system depression. The ability of the intravenous general anesthetic etomidate to modulate and activate GABAA receptors is uniquely dependent upon the beta subunit subtype present within the receptor. Receptors containing beta2- or beta3-, but not beta1 subunits, are highly sensitive to the agent. Here, chimeric beta1/beta2 subunits coexpressed in Xenopus laevis oocytes with human alpha6 and gamma2 subunits identified a region distal to the extracellular N-terminal domain as a determinant of the selectivity of etomidate. The mutation of an amino acid (Asn-289) present within the channel domain of the beta3 subunit to Ser (the homologous residue in beta1), strongly suppressed the GABA-modulatory and GABA-mimetic effects of etomidate. The replacement of the beta1 subunit Ser-290 by Asn produced the converse effect. When applied intracellularly to mouse L(tk-) cells stably expressing the alpha6beta3gamma2 subunit combination, etomidate was inert. Hence, the effects of a clinically utilized general anesthetic upon a physiologically relevant target protein are dramatically influenced by a single amino acid. Together with the lack of effect of intracellular etomidate, the data argue against a unitary, lipid-based theory of anesthesia.
Belelli,
Interaction of positive allosteric modulators with human and Drosophila recombinant GABA receptors expressed in Xenopus laevis oocytes.
1996, Pubmed,
Xenbase
Belelli,
Interaction of positive allosteric modulators with human and Drosophila recombinant GABA receptors expressed in Xenopus laevis oocytes.
1996,
Pubmed
,
Xenbase
Birnir,
A structural determinant of desensitization and allosteric regulation by pentobarbitone of the GABAA receptor.
1997,
Pubmed
Chen,
Cloning and functional expression of a Drosophila gamma-aminobutyric acid receptor.
1994,
Pubmed
,
Xenbase
Courtney,
The interactions between plasma membrane depolarization and glutamate receptor activation in the regulation of cytoplasmic free calcium in cultured cerebellar granule cells.
1990,
Pubmed
Davies,
Insensitivity to anaesthetic agents conferred by a class of GABA(A) receptor subunit.
1997,
Pubmed
Franks,
Molecular and cellular mechanisms of general anaesthesia.
1994,
Pubmed
Hadingham,
Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors.
1993,
Pubmed
,
Xenbase
Hadingham,
Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing human gamma-aminobutyric acidA receptors.
1993,
Pubmed
Hadingham,
Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors.
1996,
Pubmed
,
Xenbase
Harris,
Actions of anesthetics on ligand-gated ion channels: role of receptor subunit composition.
1995,
Pubmed
Hill-Venning,
Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor.
1997,
Pubmed
,
Xenbase
Kapur,
Pharmacological properties of gamma-aminobutyric acidA receptors from acutely dissociated rat dentate granule cells.
1996,
Pubmed
Koblin,
Polyhalogenated and perfluorinated compounds that disobey the Meyer-Overton hypothesis.
1994,
Pubmed
Liu,
Effect of n-alkane kinetics in rats on potency estimations and the Meyer-Overton hypothesis.
1994,
Pubmed
Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase
Pusch,
Rates of diffusional exchange between small cells and a measuring patch pipette.
1988,
Pubmed
Raines,
On the importance of volatile agents devoid of anesthetic action.
1994,
Pubmed
Sanna,
Differential subunit dependence of the actions of the general anesthetics alphaxalone and etomidate at gamma-aminobutyric acid type A receptors expressed in Xenopus laevis oocytes.
1997,
Pubmed
,
Xenbase
Smith,
Functional domains of GABAA receptors.
1995,
Pubmed
Stevenson,
beta-Carboline gamma-aminobutyric acidA receptor inverse agonists modulate gamma-aminobutyric acid via the loreclezole binding site as well as the benzodiazepine site.
1995,
Pubmed
,
Xenbase
Tanelian,
The role of the GABAA receptor/chloride channel complex in anesthesia.
1993,
Pubmed
Thompson,
Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination.
1996,
Pubmed
,
Xenbase
Wafford,
Functional comparison of the role of gamma subunits in recombinant human gamma-aminobutyric acidA/benzodiazepine receptors.
1993,
Pubmed
,
Xenbase
Wafford,
A novel allosteric modulatory site on the GABAA receptor beta subunit.
1994,
Pubmed
,
Xenbase
Whittemore,
Pharmacology of the human gamma-aminobutyric acidA receptor alpha 4 subunit expressed in Xenopus laevis oocytes.
1996,
Pubmed
,
Xenbase
Wingrove,
The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit.
1994,
Pubmed
,
Xenbase
Wisden,
The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon.
1992,
Pubmed
Xu,
Amino acids lining the channel of the gamma-aminobutyric acid type A receptor identified by cysteine substitution.
1993,
Pubmed
,
Xenbase
Zhu,
Delta subunit inhibits neurosteroid modulation of GABAA receptors.
1996,
Pubmed
