The role of the GABAA receptor α1 subunit N-terminal extracellular domain in propofol potentiation of chloride current

[摘要] 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 alpha 1, beta 3 and gamma 2 subunits in Xenopus oocytes to investigate the subunit dependence of propofol potentiation of pentobarbital-induced current. Pentobarbital induces current in all beta 3-subunit-containing receptors, whereas current gating by GABA requires the presence of both alpha 1 and beta 3 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. alpha 1 beta 3 gamma 2, alpha 1 beta 3, beta 3 gamma 2, or beta 3 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 alpha 1 beta 3 or alpha 1 beta 3 gamma 2 but not in beta 3 gamma 2 or beta 3 subunits, suggesting that the alpha 1 subunit was necessary for this modulatory action of propofol. Further examination of the propofol potentiation in chimeras between the alpha 1 and beta 3 subunits showed that the extracellular amino-terminal half of the alpha 1 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. (C) 1998 Elsevier Science Ltd. All rights reserved.

[发布日期] 1997-11-01

[关键词] GABA(A) receptor;pentobarbital;propofol;potentiation;subunit;Xenopus oocyte