The α and γ subunit-dependent effects of local anesthetics on recombinant GABAA receptors
The α and γ subunit-dependent effects of local anesthetics on recombinant GABAA receptors
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DOI：
10.1016/s0014-2999(00)00463-5
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发表时间：
2000-08-11
影响因子：
5
通讯作者：
Yoshiya, I
中科院分区：
文献类型：
--
作者：
Sugimoto, M;Uchida, I;Yoshiya, I
尽管局麻药全身毒性引起的惊厥被认为是由于中枢神经系统中 GABA(A) 受体相关电流的抑制所致，但其作用机制仍不清楚。因此，我们使用具有特定亚基组合的重组 GABA(A) 受体检查了局部麻醉剂对 γ-氨基丁酸 (GABA) 诱导电流的影响。小鼠 GABA(A) 受体通过将编码每个亚基的 cRNA 注射到非洲爪蟾卵母细胞中来表达。通过两电极电压钳法检查局部麻醉剂（利多卡因、布比卡因、普鲁卡因和丁卡因）对表达不同亚基组合（α1β2、α1β2γ2s、α4β2γ2s和β2）的受体的GABA诱导电流的影响。在α1β2、α1β2γ3s和α4β2γ2sGABA(A)受体上，所有局部麻醉剂均以剂量依赖性方式抑制GABA诱导的电流。 γ 2s 亚基的存在导致所有局部麻醉剂的抑制作用更大，但 α 4 亚基的存在导致抑制作用较小。在β2同聚受体处，局麻药直接诱导类似于印防己毒素的外向电流。这些数据表明（1）GABA（A）受体的α和γ亚基调节局麻药对GABA（A）功能的抑制作用，（2）局麻药可以激活β2亚基并可能阻断GABA（A）受体通道孔。 (C) 2000 Elsevier Science B.V. 保留所有权利。
Although convulsions due to local anesthetic systemic toxicity are thought to be due to inhibition of GABA(A) receptor-linked currents in the central nervous system, the mechanism of action remains unclear. We therefore examined the effects of local anesthetics on gamma-aminobutyric acid (GABA)-induced currents using recombinant GABA(A) receptors with specific combinations of subunits. Murine GABA(A) receptors were expressed by injection of cRNAs encoding each subunit into Xenopus oocytes. The effects of local anesthetics (lidocaine, bupivacaine, procaine and tetracaine) on GABA-induced currents of receptors expressing different subunit combinations (alpha 1 beta 2, alpha 1 beta 2 gamma 2s. alpha 4 beta 2 gamma 2s and beta 2) were examined via the two electrode voltage clamp method. At alpha 1 beta 2, alpha 1 beta 2 gamma 3s and alpha 4 beta 2 gamma 2s GABA(A) receptors, all local anesthetics inhibited GABA-induced currents in a dose-dependent manner. The presence of the gamma 2s subunit resulted in a greater inhibition by all local anesthetics, but the presence of the alpha 4 subunit resulted in less inhibition. At beta 2 homomeric receptors, local anesthetics directly induced an outward current similar to that of picrotoxin. These data indicated that (1) the alpha and gamma subunits of GABA(A) receptors modulated the inhibitory effects of local anesthetics on GABA(A) function, and (2) local anesthetics can activate the beta 2 subunit and may block the GABA(A) receptor channel pore. (C) 2000 Elsevier Science B.V. All rights reserved.