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调节酒精影响的机制。酒精中毒是一种慢性疾病，困扰着至少100万美国人，每年与酒精相关的费用超过1.66亿美元（NIAAA数据）。尽管它的流行和社会成本，乙醇的行动背后的分子机制尚未完全阐明。最近的研究表明，乙醇通过5 HT 3和GABA-A配体门控神经递质受体在CNS中产生许多急性和慢性效应。虽然这些受体中的每一个都可以单独介导乙醇的一些作用，但这两种受体都在一些神经元群体中表达。这些受体之间的相互作用介导乙醇的某些作用的可能性尚未研究。虽然对GABAA受体及其对乙醇的反应了解很多，但对5-HT 3受体及其如何调节乙醇的作用知之甚少。为了研究5 HT 3受体在介导乙醇作用中的重要性，关于其亚基组成、分布、功能和相互作用的信息是必不可少的。为了确定受体亚基的组成和功能，将在存在和不存在新发现的5 HT 36亚基的情况下对表达5 HT 3A亚基的转染细胞进行研究。这些研究将确定是否亚基共表达改变受体特性，并将提供洞察B亚基的作用。接下来，将确定5 HT 3受体亚基可以与转染细胞中的GABA-A受体亚基相互作用的可能性。最后，由于海马参与介导酒精的认知效应，并且5 HT 3和GABA-A受体在该区域共表达，因此将进行研究以表征培养的海马神经元中的受体亚基分布、共定位和相互作用。总之，这些研究将提供有关5 HT 3受体组成的新信息，并将为未来的研究提供工具，以阐明其在介导酒精作用中的功能。

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.