Evidence for a Common Binding Cavity for Three General Anesthetics within the GABA sub(A) Receptor

• Published in: The Journal of neuroscience Vol. 21; no. 6; pp. RC136:1 - RC136:4
• Main Authors: Jenkins, A, Greenblatt, E P, Faulkner, HJ, Bertaccini, E, Light, A, Lin, A, Andreasen, A, Viner, A, Trudell, J R, Harrison, N L
• Format: Journal Article
• Language: English
• Published: 01.03.2001
• ISSN: 0270-6474

The GABA sub(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 sub(A) receptor selectively abolish regulation by benzodiazepines and by anesthetic ethers, suggesting the existence of discrete binding sites on the GABA sub(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 Angstrom super(3). The results of the "cutoff" analysis suggest a common site of action for the anesthetics isoflurane, halothane, and chloroform on the GABA sub(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.