GABAA receptors: function, physiology and involvement in anesthesia

摘要 γ-氨基丁酸A型受体是一种离子亲和性抑制离子通道。通过以下途径进行抑制 GABAA受体决定大脑的活动水平，而在单个细胞中，它决定了倾向 对兴奋性输入做出反应的细胞的动作电位。GABAA受体是一个主要的靶点 静脉麻醉剂和许多内源性化合物，包括神经活性类固醇。这个项目 将研究内源性化合物和临床化合物的组合如何影响本地人的功能 GABAA受体，并启动麻醉的起效和解除。具体地说，我们将：i)探索动力学和 激活和调节天然突触和突触外GABA受体的能量学方面 临床相关化合物；ii)确定内源性神经类固醇在临床作用中的作用 以检验类固醇水平的正常生理变化会改变 对麻醉药的反应；iii)探索从麻醉中可控恢复的方法；以及iv)测试 使用GABAA受体的部分变构激动剂作为安全、温和的镇静剂。

ABSTRACT The γ-aminobutyric acid type A (GABAA) receptor is an ionotropic inhibitory ion channel. Inhibition mediated by GABAA receptors sets the level of activity in the brain, whereas in individual cells it determines the propensity of a cell to fire an action potential in response to excitatory input. The GABAA receptor is a major target for intravenous anesthetics and numerous endogenous compounds including neuroactive steroids. This project will investigate how combinations of endogenous and clinical compounds affect the functioning of the native GABAA receptor, and initiate the onset and offset of anesthesia. Specifically, we will: i) explore the kinetic and energetic aspects of activation and modulation of native synaptic and extrasynaptic GABAA receptors by clinically-relevant compounds; ii) determine the involvement of endogenous neurosteroids in the clinical actions of intravenous anesthetics to test the hypothesis that normal physiological changes in steroid levels modify responses to anesthetics; iii) probe ways for controllable recovery from anesthesia; and iv) test the feasibility of using partial allosteric agonists of the GABAA receptor as safe, mild sedatives.