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NEUROPHARMACOLOGY
1 Subunit with Near-Normal Apparent Affinity for GABA: Characterization in Heterologous Systems and Production of Knockin Mice
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas (C.M.B., L.A.H., Y.A.B., R.A.H.); Departments of Anesthesiology and Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania (D.F.W., G.E.H.); C.V. Starr Laboratory for Molecular Neuropharmacology, Departments of Anesthesiology and Pharmacology, Weill Medical College, Cornell University, New York, New York (N.T., N.V.B., N.L.H.); Department of Psychology, State University of New York, Binghamton, New York (S.L.B.); and Department of Anesthesiology, University of Wisconsin, Madison, Wisconsin (A.S., S.D., R.A.P.)
Volatile anesthetics and alcohols enhance transmission mediated by 
-aminobutyric acid type A receptors (GABAARs) in the central nervous system, an effect that may underlie some of the behavioral actions of these agents. Substituting a critical serine residue within the GABAAR 
1 subunit at position 270 with the larger residue histidine eliminated receptor modulation by isoflurane, but it also affected receptor gating (increased GABA sensitivity). To correct the shift in GABA sensitivity of this mutant, we mutated a second residue, leucine at position 277 to alanine. The double mutant 1(S270H,L277A)
22S GABAAR was expressed in Xenopus laevis oocytes and human embryonic kidney (HEK)293 cells, and it had near-normal GABA sensitivity. However, rapid application of a brief GABA pulse to receptors expressed in HEK293 cells revealed that the deactivation was faster in double mutant than in wild-type receptors. In all heterologous systems, the enhancing effect of isoflurane and ethanol was greatly decreased in the double mutant receptor. Homozygous knockin mice harboring the double mutation were viable and presented no overt abnormality, except hyperactivity. This knockin mouse line should be useful in determining which behavioral actions of volatile anesthetics and ethanol are mediated by the GABAARs containing the 1 subunit.
Address correspondence to: Dr. R. Adron Harris, Waggoner Center for Alcohol and Addiction Research, 1 University Station A4800, University of Texas at Austin, Austin, TX 78712-0159. E-mail: harris{at}mail.utexas.edu
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