GABAA receptors: function, physiology and involvement in anesthesia

GABAA 受体：功能、生理学和麻醉作用

• 批准号: 10582956
• 负责人: GUSTAV AKK
• 金额: $ 1.21万
• 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/10582956
• 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; receptor function; 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) 受体是一种离子型抑制离子通道。抑制介导 GABAA 受体决定大脑的活动水平，而在单个细胞中它决定倾向 细胞响应兴奋性输入而激发动作电位。 GABAA 受体是主要靶点 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 将研究内源性和临床化合物的组合如何影响天然化合物的功能 GABAA 受体，并启动麻醉的开始和结束。具体来说，我们将：i）探索动力学和 天然突触和突触外 GABAA 受体的激活和调节的能量方面 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参与 静脉麻醉药来检验类固醇水平的正常生理变化会改变的假设 对麻醉剂的反应； iii) 探讨从麻醉中可控恢复的方法； iv) 测试可行性 使用 GABAA 受体部分变构激动剂作为安全、温和的镇静剂。