Mapping the Foci of Arrestin's Role in Ethanol Sedation

描述(由申请人提供)：本提案的目标是为控制酒精镇静的过程开发一个遗传框架。这个框架将通过对果蝇中几个已定义的信号突变体的上位性分析来产生。这个框架将以非视觉的果蝇arrestin Kurtz为中心，并将定义调节行为对酒精敏感性的遗传交互作用。库尔茨的突变体对酒精的镇静作用过敏。这种敏感性被神经系统内库尔茨基因的靶向表达所拯救，表明在正常的酒精醉人特性抵抗中，神经需要芳香素活性。拟议中的实验将检验这一要求是否是库尔茨的一种发育功能，或者芳香素活性的缺乏是否会使神经系统对酒精的镇静作用产生生理上的敏感。这些实验还将通过功能获得性救援实验，为库尔茨调节酒精镇静的功能定位神经焦点。随着对库尔茨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生过程中与库尔茨相互作用的其他分子。已经证实了一种这样的相互作用，即krz1突变可以抑制Rutabaga型腺酰环酶的酒精敏感性表型。从这些实验中获得的数据将提供改变动物对酒精敏感性的分子过程的功能解剖。

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.