GABAA receptors: function, physiology and involvement in anesthesia

GABAA 受体：功能、生理学和麻醉作用

• 批准号: 10620344
• 负责人: GUSTAV AKK
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620344
• 关键词: Action Potentials; Affect; Agonist; Anesthesia procedures; Anesthetics; Brain; Cells; Clinical; Fire - disasters; Individual; Intravenous Anesthetics; Ion Channel; Kinetics; Mediating; Physiological; Physiology; Recovery; Steroids; Synapses; Testing; clinically relevant; feasibility testing; gamma-Aminobutyric Acid; neurosteroids; receptor; response; sedative

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.

抽象的 γ-氨基丁酸A型（GABAA）受体是离子抑制离子通道。介导的抑制作用 GABAA受体设定了大脑的活性水平，而在单个细胞中，它决定了前景 响应兴奋性输入的细胞发射动作潜力。 GABAA接收器是 静脉麻醉药和许多内源性化合物，包括神经活性类固醇。这个项目 将研究内源性和临床化合物的组合如何影响天然的功能 GABAA受体，并启动麻醉的发作和抵消。具体来说，我们将：i）探索动力学和 激活和调节天然突触和外突性GABAA受体的能量方面 临床上与临床相关的化合物； ii）确定内源性神经素参与临床作用 静脉麻醉药以测试类固醇水平正常生理变化的假设可改变 对麻醉剂的反应； iii）探测从麻醉中恢复的方法；和iv）测试可行性 使用GABAA受体的部分变构激动剂作为安全，温和的镇静剂。