Evidence for a common binding cavity for three general anesthetics within the GABA(A) receptor

The GABA(A) receptor is an important target for a variety of general anesth etics (Franks and Lieb, 1994) and for benzodiazepines such as diazepam. Spe cific point mutations in the GABA(A) receptor selectively abolish regulatio n by benzodiazepines (Rudolph et al., 1999; McKernan et al., 2000) and by a nesthetic 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 mutagenes is of specific amino acid side chains, we estimate the volume of a proposed anesthetic binding site as between 250 and 370 Angstrom (3). The results o f the "cutoff" analysis suggest a common site of action for the anesthetics isoflurane, halothane, and chloroform on the GABA(A) receptor. Moreover, t he data support a crucial role for Leu232, Ser270, and Ala291 in the alpha subunit in defining the boundaries of an amphipathic cavity, which can acco mmodate a variety of small general anesthetic molecules.