Mapping the Foci of Arrestin's Role in Ethanol Sedation

描述（由申请人提供）：本提案的目的是开发控制酒精镇静过程的遗传框架。该框架将通过对果蝇中几个定义的信号突变体的上位性分析产生。这个框架将以果蝇的非视觉捕捉库尔兹为中心，并将定义调节对酒精行为敏感性的基因相互作用。库尔兹突变体对酒精的镇静作用非常敏感。神经系统中kurtz cDNA的靶向表达挽救了这种敏感性，证明了在正常抵抗酒精令人陶醉的特性时，神经系统需要抑制素活动。拟议的实验将检验这种需求是库尔茨的发育功能，还是抑制素活性的缺乏使神经系统在生理上对酒精的镇静作用敏感。本实验还将通过功能获得救援实验绘制kurtz调节酒精镇静功能的神经焦点。随着对kurtz在何时何地调节酒精敏感性的深入了解，我们将定义在酒精中毒发展过程中与kurtz相互作用的其他分子。其中一种相互作用，即krz1突变可以抑制芜菁i型腺苷基环化酶的酒精敏感性表型，已经得到证实。从这些实验中获得的数据将为改变动物对酒精敏感性的分子过程提供功能解剖。

DESCRIPTION (provided by applicant): The objective of this proposal is to develop a genetic framework for the processes controlling alcohol sedation. The framework will be produced through epistasis analysis on several defined signaling mutants in Drosophila. This framework will center on the Drosophila non-visual arrestin kurtz, and will define genetic interactions that modulate behavioral sensitivity to alcohol. Mutants in kurtz are hypersensitive to the sedative effects alcohol. This sensitivity is rescued by the targeted expression of a kurtz cDNA within the nervous system, demonstrating a neural requirement for arrestin activity in the normal resistance to alcohol's intoxicating properties. The proposed experiments will examine whether this requirement is a developmental function of kurtz, or whether the absence of arrestin activity leaves the nervous system physiologically sensitized to the sedative effects of alcohol. The experiments will also map the neural foci for the function of kurtz in regulating alcohol sedation through gain-of-function rescue experiments. With this deeper understanding of where and when kurtz functions to modulate alcohol sensitivity, we will define additional molecules that interact with kurtz in the development of alcohol intoxication. One such interaction, in which the krz1 mutation can repress the alcohol sensitivity phenotype of the rutabaga typeI adenylyl cylase, has already been demonstrated. The data gained from these expriements will provide a functional dissection of the molecular processes that modify an animal's sensitivity to alcohol.