Uchida I, Li L, Yang J
Department of Anesthesiology, University of Rochester Medical Center, NY 14642, USA.
Neuropharmacology. 1997 Nov-Dec;36(11-12):1611-21. doi: 10.1016/s0028-3908(97)00180-9.
Propofol (2,6-diisopropylphenol), an intravenous general anesthetic in active clinical use today, potentiates the action of gamma-aminobutyric acid (GABA) at the type-A receptor and also directly induces current in the absence of GABA. We expressed different combinations of murine GABA(A) receptor alpha1, beta3 and gamma2 subunits in Xenopus oocytes to investigate the subunit dependence of propofol potentiation of pentobarbital-induced current. Pentobarbital induces current in all beta3-subunit-containing receptors, whereas current gating by GABA requires the presence of both alpha1 and beta3 subunits. Therefore, pentobarbital rather than GABA was used to induce current in order to separate the subunit dependence of current gating from the subunit dependence of potentiating action of propofol. alpha1beta3gamma2, alpha1beta3, beta3gamma2, or beta3 subunit combinations all responded to pentobarbital in a dose-dependent manner. True potentiation was defined as the current magnitude to simultaneous application of pentobarbital and propofol exceeding the additive responses to individual drug applications. A dose-dependent propofol potentiation of pentobarbital-induced current was observed in oocytes injected with alpha1beta3 or alpha1beta3gamma2 but not in beta3gamma2 or beta3 subunits, suggesting that the alpha1 subunit was necessary for this modulatory action of propofol. Further examination of the propofol potentiation in chimeras between the alpha1 and beta3 subunits showed that the extracellular amino-terminal half of the alpha1 subunit was sufficient to support propofol potentiation. The different requirements of the receptor structure for the agonistic (gating) and the potentiating actions suggest that these two actions of propofol are distinct processes mediated through its action at distinct sites.
丙泊酚（2,6 - 二异丙基苯酚）是目前临床上正在使用的一种静脉全身麻醉药，它可增强γ-氨基丁酸（GABA）在A型受体上的作用，并且在没有GABA的情况下也能直接诱导电流。我们在非洲爪蟾卵母细胞中表达了小鼠GABA(A)受体α1、β3和γ2亚基的不同组合，以研究丙泊酚增强戊巴比妥诱导电流的亚基依赖性。戊巴比妥能在所有含β3亚基的受体中诱导电流，而GABA引发电流则需要α1和β3亚基同时存在。因此，为了将电流开启的亚基依赖性与丙泊酚增强作用的亚基依赖性区分开来，我们使用戊巴比妥而非GABA来诱导电流。α1β3γ2、α1β3、β3γ2或β3亚基组合对戊巴比妥均有剂量依赖性反应。真正的增强作用定义为同时应用戊巴比妥和丙泊酚时的电流幅度超过单独应用每种药物时的累加反应。在注射了α lβ3或α1β3γ2的卵母细胞中观察到丙泊酚对戊巴比妥诱导电流有剂量依赖性增强作用，而在β3γ2或β3亚基中未观察到，这表明α1亚基是丙泊酚这种调节作用所必需的。对α1和β3亚基之间嵌合体中丙泊酚增强作用的进一步研究表明，α1亚基的细胞外氨基末端一半足以支持丙泊酚的增强作用。受体结构对激动（开启）作用和增强作用的不同要求表明，丙泊酚的这两种作用是通过其在不同位点的作用介导的不同过程。
