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Distinct Loci Mediate the Direct and Indirect Actions of the Anesthetic Etomidate at GABA A Receptors
Author(s) -
Moody Eric J.,
Knauer Christopher,
Granja Ricardo,
Strakhova Marina,
Skolnick Phil
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.69031310.x
Subject(s) - etomidate , gabaa receptor , receptor , flunitrazepam , anesthetic , chemistry , aminobutyric acid , chloride channel , gamma aminobutyric acid , protein subunit , pharmacology , amino acid , biology , biochemistry , medicine , anesthesia , propofol , gene
Most general anesthetics produce two distinct actions at GABA A receptors. Thus, these drugs augment GABA‐gated chloride currents (referred to as an indirect action) and, at higher concentrations, elicit chloride currents in the absence of GABA (referred to as a direct action). Because a β subunit appears to be required for the direct action of intravenous anesthetics in recombinant GABA A receptors, site‐directed mutagenesis of the β3 subunit was performed to identify amino acid residues that are critical for this action. In HEK293 cells expressing a prototypical GABA A receptor composed of α1β3γ2 subunits, mutation of amino acid 290 from Asn to Ser dramatically reduced both etomidate‐induced chloride currents and its ability to stimulate [ 3 H]flunitrazepam binding. By contrast, the ability of etomidate to augment GABA‐gated chloride currents and GABA‐enhanced [ 3 H]flunitrazepam binding was retained. The demonstration that the direct, but not the indirect, actions of etomidate are dependent on β3(Asn 290 ) indicates that the dual actions of this intravenous anesthetic at GABA A receptors are mediated via distinct loci.