Single Channel Characterization of Ethanol Action on the Glycine Receptor

描述（由申请人提供）：了解乙醇在整个大脑和中枢神经系统中的作用机制和目标是了解乙醇复杂药理学的关键部分。乙醇的多种靶标中有甘氨酸受体（GlyR）；一种抑制性的配体门控离子通道，在脑干和脊髓以及大脑高级区域（包括与成瘾有关的区域）大量表达。尽管有许多研究考察了乙醇对甘氨酸受体的影响，但在分子水平上表征其作用的研究却很少。我们建议利用膜片钳电生理学研究乙醇对野生型GlyR单通道特性的影响，并利用靶向突变进一步了解乙醇增强GlyR功能的机制。长期目标是提供一个分子框架，以了解乙醇对中枢神经系统中GlyR群体的作用，以及乙醇对GlyR的调节如何促进其体内效应。这项拟议的研究为实现这一理解提供了明确的一步，目的是具体证明乙醇如何在单通道水平上增强GlyR功能。为了开发适当和有效的酒精中毒治疗方法，有必要了解乙醇如何在全身发挥其作用。这项研究不仅能找到更好的治疗酒精中毒的方法，还能加深我们对酒精在整个中枢神经系统中的作用的理解。

DESCRIPTION (provided by applicant): Understanding the mechanisms and targets of ethanol's actions throughout the brain and central nervous system is a critical piece in the quest to understand the complex pharmacology of ethanol. Among ethanol's diverse targets is the glycine receptor (GlyR); an inhibitory, ligand gated ion channel that is found heavily expressed throughout the brain stem and spinal cord in addition to higher brain regions, including those involved in addiction. Despite numerous studies examining the effects of ethanol on the glycine receptor, very little has been done to characterize its actions on the molecular level. We propose to use patch clamp electrophysiology to investigate the effects of ethanol on the single channel properties of the wild-type GlyR and use targeted mutations to further understand the mechanisms of ethanol enhancement of GlyR function. The long-range goal is to provide a molecular framework for understanding ethanol's actions on the GlyR population within the central nervous system and how ethanol's modulation of the GlyR contributes to its in vivo effects. This proposed research provides a definitive step towards attaining this understanding with the objective of demonstrating specifically how ethanol enhances GlyR function at the single channel level. In order to develop appropriate and effective treatments of alcoholism it is necessary to understand how ethanol exerts its effects throughout the body. This research could not only lead to better treatments for alcoholism, but will enhance our understanding of alcohol's actions throughout the central nervous system.