5HT3 Receptors: Composition, Distribution, Interactions

描述(由申请人提供)： 我们研究的长期目标是深入了解酒精影响的调节机制。酒精中毒是一种慢性疾病，至少有100万美国人受到影响，每年与酒精相关的费用超过1.66亿美元(NIAAA的数据)。尽管乙醇的流行和社会成本很高，但乙醇作用的分子机制尚未完全阐明。最近的研究表明，乙醇在中枢神经系统中通过5HT3和GABA-A配体门控的神经传递受体产生许多急性和慢性影响。虽然这些受体中的每一个单独都可以介导乙醇的一些作用，但这两种受体在某些神经元群体中都有表达。这些受体之间的串扰是否可能介导乙醇的某些作用还没有被研究过。尽管人们对GABAA受体及其对乙醇的反应了解很多，但对5-HT3受体或它如何调节乙醇的作用知之甚少。为了研究5HT3受体在介导乙醇作用中的重要性，了解其亚单位的组成、分布、功能和相互作用是必不可少的。为了确定受体亚单位的组成和功能，将在新发现的5HT36亚单位存在和不存在的情况下，对表达5HT3A亚单位的转基因细胞进行研究。这些研究将确定亚单位共表达是否会改变受体的特性，并将为深入了解B亚单位的作用提供依据。接下来，将确定5HT3受体亚基与转基因细胞中GABA-A受体亚基相互作用的可能性。最后，由于海马区参与调节酒精的认知效应，且5HT3和GABA-A受体在该区域共表达，因此将进行海马神经元培养中受体亚单位的分布、共定位和相互作用的研究。总之，这些研究将提供有关5HT3受体组成的新信息，并将为未来的研究提供工具，以阐明其在调节酒精行为中的作用。

DESCRIPTION (provided by applicant): The long term goal of our studies is to gain insight into mechanisms mediating the effects of alcohol. Alcoholism is a chronic disorder that afflicts at least 1 million Americans and exacts a cost of over 166 million dollars per year (NIAAA data) in alcohol-related expenses. Despite its prevalence and cost to society, the molecular mechanisms underlying the actions of ethanol have not been fully elucidated. Recent studies suggest that ethanol produces many of its acute and chronic effects in the CNS through the 5HT3 and GABA-A ligand-gated neurotransmifter receptors. Although each of these receptors alone can mediate some of the actions of ethanol, both receptors are expressed in some neuronal populations. The possibility that cross-talk between these receptors mediates some of the actions of ethanol has not yet been studied. Although much is known about the GABAA receptor and its responses to ethanol, little is known about the 5-HT3 receptor or how it modulates the actions of ethanol. To investigate the importance of 5HT3 receptors in mediating the actions of ethanol, information concerning its subunit composition, distribution, function, and interactions is essential. To determine receptor subunit composition and function, studies will be performed on transfected cells expressing the 5HT3A subunit in the presence and absence of the newly discovered 5HT36 subunit. These studies will determine whether subunit coexpression alters receptor properties and will provide insight into the role of the B subunit. Next, the possibility that the 5HT3 receptor subunits can interact with GABA-A receptor subunits in transfected cells will be determined. Finally, since the hippocampus is involved in mediating the cognitive effects of alcohol, and 5HT3 and GABA-A receptors are coexpressed in this region, studies will be performed to characterize receptor subunit distribution, colocalization and interactions in hippocampal neurons in culture. Together, these studies will provide novel information concerning 5HT3 receptor composition and will provide tools for future research to elucidate its function in mediating the actions of alcohol.