Jenkins A, Greenblatt E P, Faulkner H J, Bertaccini E, Light A, Lin A, Andreasen A, Viner A, Trudell J R, Harrison N L
C. V. Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York 10021, USA.
J Neurosci. 2001 Mar 15;21(6):RC136. doi: 10.1523/JNEUROSCI.21-06-j0002.2001.
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.
GABA(A)受体是多种全身麻醉药（弗兰克斯和利布，1994年）以及地西泮等苯二氮䓬类药物的重要作用靶点。GABA(A)受体的特定点突变可选择性地消除苯二氮䓬类药物（鲁道夫等人，1999年；麦肯南等人，2000年）和麻醉性醚类药物（米希克等人，1997年；克拉索夫斯基等人，1998年；科尔奇内等人，1999年）的调节作用，这表明GABA(A)受体上存在这些药物的离散结合位点。我们使用不同分子大小的麻醉药（异氟烷＞氟烷＞氯仿）以及特定氨基酸侧链的互补诱变技术，估计了一个假定的麻醉药结合位点的体积在250至370 ų之间。“截断”分析结果表明，异氟烷、氟烷和氯仿等麻醉药在GABA(A)受体上有共同的作用位点。此外，数据支持α亚基中的亮氨酸232、丝氨酸270和丙氨酸291在界定一个可容纳多种小全身麻醉药分子的两亲性腔室边界方面起着关键作用。
