Evidence for a common binding cavity for three general anesthetics within the GABAA receptor.
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.
Jenkins
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C. V. Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York 10021, USA. anj2005@med.cornell.edu
Greenblatt
E P
EP
Faulkner
H J
HJ
Bertaccini
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E
Light
A
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Lin
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A
Andreasen
A
A
Viner
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A
Trudell
J R
JR
Harrison
N L
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D000777:Anesthetics / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002725:Chloroform / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006221:Halothane / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007530:Isoflurane / Q000737:chemistry / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection
D000777:Anesthetics; D011963:Receptors, GABA-A; D002725:Chloroform; D007530:Isoflurane; D006221:Halothane