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靶点是了解乙醇复杂药理学的关键。乙醇的不同靶点是甘氨酸受体（GlyR）;一种抑制性配体门控离子通道，除了高级大脑区域外，还在整个脑干和脊髓中大量表达，包括参与成瘾的区域。尽管有许多研究探讨乙醇对甘氨酸受体的影响，但很少有人在分子水平上表征其作用。我们建议使用膜片钳电生理学研究乙醇对野生型GlyR的单通道特性的影响，并使用靶向突变来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内GlyR群体的作用，以及乙醇对GlyR的调节如何有助于其体内效应。这项拟议的研究为实现这一理解提供了明确的一步，其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整个身体中发挥作用。这项研究不仅可以更好地治疗酒精中毒，而且将增强我们对酒精在整个中枢神经系统中作用的理解。

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.