1. Evidence for a common binding cavity for three general anesthetics within the GABAA receptor
- Author
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James R. Trudell, Eric P. Greenblatt, Anna Viner, H J Faulkner, Adam Light, Andrew Jenkins, Audrey Lin, Edward J. Bertaccini, Neil L. Harrison, and Alyson Andreasen
- Subjects
Patch-Clamp Techniques ,Kidney ,Transfection ,Cell Line ,Structure-Activity Relationship ,medicine ,Humans ,Binding site ,Receptor ,G alpha subunit ,Anesthetics ,chemistry.chemical_classification ,Binding Sites ,Dose-Response Relationship, Drug ,Isoflurane ,Chemistry ,GABAA receptor ,General Neuroscience ,Receptors, GABA-A ,Amino acid ,Anesthesia ,Anesthetic ,Biophysics ,Mutagenesis, Site-Directed ,Chloroform ,Halothane ,Rapid Communication ,medicine.drug - Abstract
The GABA(A) receptor is an important target for a variety of general anesthetics (Franks and Lieb, 1994) and for benzodiazepines such as diazepam. Specific point mutations in the GABA(A) receptor selectively abolish regulation by benzodiazepines (Rudolph et al., 1999; McKernan et al., 2000) and by anesthetic ethers (Mihic et al., 1997; Krasowski et al., 1998; Koltchine et al., 1999), suggesting the existence of discrete binding sites on the GABA(A) receptor for these drugs. Using anesthetics of different molecular size (isoflurane > halothane > chloroform) together with complementary mutagenesis of specific amino acid side chains, we estimate the volume of a proposed anesthetic binding site as between 250 and 370 A(3). The results of the "cutoff" analysis suggest a common site of action for the anesthetics isoflurane, halothane, and chloroform on the GABA(A) receptor. Moreover, the data support a crucial role for Leu232, Ser270, and Ala291 in the alpha subunit in defining the boundaries of an amphipathic cavity, which can accommodate a variety of small general anesthetic molecules.
- Published
- 2001