Distinct Loci Mediate the Direct and Indirect Actions of the Anesthetic Etomidate at GABAA Receptors |
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Authors: | † Eric J Moody †Christopher Knauer Ricardo Granja Marina Strakhova †Phil Skolnick |
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Institution: | Laboratory of Neuroscience, NIDDK, National Institutes of Health, Bethesda, and; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland, U.S.A. |
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Abstract: | Abstract: Most general anesthetics produce two distinct actions at GABAA 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 GABAA 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 GABAA 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 3H]flunitrazepam binding. By contrast, the ability of etomidate to augment GABA-gated chloride currents and GABA-enhanced 3H]flunitrazepam binding was retained. The demonstration that the direct, but not the indirect, actions of etomidate are dependent on β3(Asn290) indicates that the dual actions of this intravenous anesthetic at GABAA receptors are mediated via distinct loci. |
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Keywords: | Etomidate Anesthetics GABAA receptors Chloride currents Flunitrazepam |
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