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The Journal of Neuroscience, 2001, 21:RC136:1-4

RAPID COMMUNICATION
Evidence for a Common Binding Cavity for Three General Anesthetics within the GABA_A Receptor

Andrew Jenkins¹, Eric P. Greenblatt², Howard J. Faulkner³, Edward Bertaccini⁴, Adam Light⁵, Audrey Lin⁵, Alyson Andreasen¹, Anna Viner¹, James R. Trudell⁴, and Neil L. Harrison¹

¹ C. V. Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York 10021, ² Department of Anesthesia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, ³ Imperial College School of Medicine, London SW7 2AZ, United Kingdom, ⁴ Department of Anesthesia, Stanford University School of Medicine, Stanford, California 94305, and ⁵ The University of Chicago, Chicago, Illinois 60637

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 Å³. 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  subunit in defining the boundaries of an amphipathic cavity, which can accommodate a variety of small general anesthetic molecules.

Key words: anesthetic; GABA; binding site; allosteric; receptor; molecular volume

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Copyright © Society for Neuroscience  0270-6474//$05.00/0

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