STRUCTURAL BASIS OF ALCOHOL ACTION ON GLYCINE RECEPTORS

University Of Colorado Denver, Aurora CO

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Abstract

The behavioral and cognitive changes induced by ethanol have recently been traced to alterations in the activity of several neurotransmitter- gated ion channels. It has been hypothesized that alcohols bind specifically to these proteins, altering their conformation and ability to transport ions across membranes. This hypothesis may now be addressed by determining the effect of alcohols on the conformation and ligand binding properties of neurotransmitter receptors. In this project we use multidimensional heteronuclear magnetic resonance spectroscopy to focus on the atomic-resolution structure of the strychnine-sensitive glycine receptor whose involvement in the central depressant effects of ethanol has recently been established. We will focus on a extracellular domain of the glycine receptor due to its size, apparent solubility and ability to bind glycine, strychnine, and ethanol. The structural and biochemical results of this project will provide a detailed mechanism of alcohol action and aid in the design of novel compounds that combat the depressant and addictive effects of alcohol.