Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (Y.L., X.L., Y.J., S.A.F., H.-J.F.); Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China (Y.L.); and Department of Anesthesia, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (X.L.).
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (Y.L., X.L., Y.J., S.A.F., H.-J.F.); Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China (Y.L.); and Department of Anesthesia, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (X.L.)
J Pharmacol Exp Ther. 2019 Jan;368(1):100-105. doi: 10.1124/jpet.118.252403. Epub 2018 Nov 2.
Central 4 receptors are the most abundant isoform of subunit-containing extrasynaptic GABA receptors that mediate tonic inhibition. Although the amplitude of GABA-activated currents through 4 receptors is modulated by multiple general anesthetics, the effects of general anesthetics on desensitization and deactivation of 4 receptors remain unknown. In the current study, we investigated the effect of etomidate, a potent general anesthetic, on the kinetics and the pseudo steady-state current amplitude of 43 receptors inducibly expressed in human embryonic kidney 293 TetR cells. Etomidate directly activates 43 receptors in a concentration-dependent manner. Etomidate at a clinically relevant concentration (3.2 M) enhances maximal response without altering the EC of GABA concentration response. Etomidate also increases the extent of desensitization and prolongs the deactivation of 43 receptors in the presence of maximally activating concentrations of GABA (1 mM). To mimic the modulatory effect of etomidate on tonic currents, long pulses (30-60 seconds) of a low GABA concentration (1 M) were applied to activate 43 receptors in the absence and presence of etomidate. Although etomidate increases the desensitization of 43 receptors, the pseudo steady-state current amplitude at 1 M GABA is augmented by etomidate. Our data demonstrate that etomidate enhances the pseudo steady-state current of 43 receptors evoked by a GABA concentration comparable to an ambient GABA level, suggesting that 43 receptors may mediate etomidate's anesthetic effect in the brain.
中央 4 型受体是含有亚基的突触外 GABA 受体中最丰富的同工型，介导紧张性抑制。虽然 4 型受体介导的 GABA 激活电流幅度可被多种全身麻醉药调节，但全身麻醉药对 4 型受体脱敏和失活的影响尚不清楚。在本研究中，我们研究了依托咪酯（一种强效的全身麻醉药）对人胚肾 293 TetR 细胞中可诱导表达的 43 型受体动力学和准稳态电流幅度的影响。依托咪酯以浓度依赖性方式直接激活 43 型受体。依托咪酯在临床相关浓度（3.2μM）下增强最大反应，而不改变 GABA 浓度反应的 EC。依托咪酯还增加了 GABA（1mM）最大激活浓度下 43 型受体的脱敏程度并延长失活时间。为了模拟依托咪酯对紧张性电流的调节作用，在无依托咪酯和有依托咪酯的情况下，应用低 GABA 浓度（1μM）的长脉冲（30-60 秒）激活 43 型受体。尽管依托咪酯增加了 43 型受体的脱敏，但依托咪酯增强了 1μM GABA 时的准稳态电流幅度。我们的数据表明，依托咪酯增强了与环境 GABA 水平相当的 GABA 浓度下 43 型受体诱发的准稳态电流，这表明 43 型受体可能介导依托咪酯在大脑中的麻醉作用。
