1997
DOI: 10.1073/pnas.94.20.11031
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The interaction of the general anesthetic etomidate with the γ-aminobutyric acid type A receptor is influenced by a single amino acid

Abstract: The ␥-aminobutyric acid type A (GABA A ) 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 (␣ 1-6 , ␤ 1-3 , ␥ 1-3 , ␦ 1 , and 1 ). Positive allosteric modulation of GABA A 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 … Show more

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Cited by 360 publications
(342 citation statements)
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“…In addition, aliphatic carbocation intermediates are known to be highly reactive with water (t1 ⁄ 2 Ͻ1 ns (25)), further limiting the possibility of diffusional encounters with reactive side chains distant from the binding site. That the photolabeling of ␣1Met-236 and ␤Met-286 was potentiated in the presence of GABA, fully inhibitable by etomidate (12), and inhibitable by propofol 6 provides further evidence that [ 3 H]azietomidate is acting as a specific affinity label and that the photolabeling results provide a direct identification of two amino acids contributing to the etomidate binding site.…”
Section: Photoaffinity Labeling With [mentioning
confidence: 70%
“…In addition, aliphatic carbocation intermediates are known to be highly reactive with water (t1 ⁄ 2 Ͻ1 ns (25)), further limiting the possibility of diffusional encounters with reactive side chains distant from the binding site. That the photolabeling of ␣1Met-236 and ␤Met-286 was potentiated in the presence of GABA, fully inhibitable by etomidate (12), and inhibitable by propofol 6 provides further evidence that [ 3 H]azietomidate is acting as a specific affinity label and that the photolabeling results provide a direct identification of two amino acids contributing to the etomidate binding site.…”
Section: Photoaffinity Labeling With [mentioning
confidence: 70%
“…GABA A receptor residues that are photolabeled by etomidate derivatives (13,14), in both ␣-M1 and ␤-M3, are highlighted in pink. We also illustrate ␤2Asn-265 on ␤-M2, a residue where mutations influence etomidate sensitivity (37,38).…”
Section: Chemicals-r-(ϩ)-etomidate Was Obtained From Bedford Laboratomentioning
confidence: 99%
“…In the 100 lowest energy docking orientations in the binding sites at GABA A receptor ␤2-M3/␣1-M1 interfaces, the etomidate molecule is oriented with the benzene ring located near ␤2-M2. In the lowest energy poise, the non-branching nitrogen in the imidazole group is located 3.0 Å from the amide nitrogen of ␤2N265 (M2-15Ј), a residue where mutations affect etomidate sensitivity (37,38). The ester leaving group (ethanol) projects outward from the ion channel toward the lipid-protein interface between ␣1-M1 and ␤2-M3.…”
Section: Etomidate Docking To a Molecular Structure Homologymentioning
confidence: 99%
“…This patient showed a decreased sensitivity to etomidate and propofol. In studies on recombinant receptors, mutations at amino acid 265 in the second and amino acid 286 in the third transmembrane region of the GABA A receptor b subunits b1, b2, and b3 have been demonstrated to render GABA A receptors largely insensitive to etomidate and/or propofol action in vitro (Belelli et al, 1997;Krasowski et al, 1998;Siegwart et al, 2002). We therefore sequenced these regions in all three b subunit genes, but were unable to detect a mutation that would cause an amino-acid change.…”
Section: Discussionmentioning
confidence: 99%
“…Propofol potentiation of GABA-induced currents was abolished by a point mutation in the GABA A receptor b1 subunit (Krasowski et al, 1998). Etomidate has also been shown to influence the function of recombinant human GABA A receptors in vitro (Belelli et al, 1997).…”
Section: Introductionmentioning
confidence: 99%