Hauser C A, Wetzel C H, Berning B, Gerner F M, Rupprecht R
Max Planck Institute of Psychiatry, Clinical Institute, Kraepelinstrasse 10, 80804 Munich, Federal Republic of Germany.
J Biol Chem. 1997 May 2;272(18):11723-7. doi: 10.1074/jbc.272.18.11723.
gamma-Aminobutyric acid type A (GABAA) receptor subtypes containing the alpha6-subunit are generally thought to be insensitive to the action of benzodiazepine agonists. We describe the specific binding of the benzodiazepine agonist flunitrazepam to alpha6beta2gamma2-containing GABAA receptors, which has not been observed before and differs from previous reports. With the whole-cell voltage-clamp technique, we observed a functional discrimination between alpha1beta2gamma2- and alpha6beta2gamma2-receptors. Different benzodiazepines had different effects on GABA-evoked chloride currents. The agonist flunitrazepam had an inverse agonistic effect, whereas the antagonist flumazenil increased GABA-induced chloride currents. The action of flunitrazepam on the channel activity of alpha6beta2gamma2-receptors was opposite to its action on alpha1beta2gamma2-receptors. We conclude that flunitrazepam can act as either an agonist or an inverse agonist, depending on the GABAA receptor configuration.
一般认为，含有α6亚基的A型γ-氨基丁酸（GABAA）受体亚型对苯二氮䓬类激动剂的作用不敏感。我们描述了苯二氮䓬类激动剂氟硝西泮与含有α6β2γ2的GABAA受体的特异性结合，这在此前未被观察到且与先前报道不同。采用全细胞膜片钳技术，我们观察到α1β2γ2受体和α6β2γ2受体之间存在功能差异。不同的苯二氮䓬类药物对GABA诱发的氯离子电流有不同影响。激动剂氟硝西泮具有反向激动作用，而拮抗剂氟马西尼则增加GABA诱导的氯离子电流。氟硝西泮对α6β2γ2受体通道活性的作用与其对α1β2γ2受体的作用相反。我们得出结论，氟硝西泮可根据GABAA受体的构型充当激动剂或反向激动剂。
