The Function of Arrestin in Drosophila Behavior

描述(申请人提供)：动物从环境中获得的大部分信息是通过G蛋白偶联受体(GPCRs)收集的。为了对环境有一个准确的感知，减弱这些受体的信号的能力是最可取的。此外，突触可塑性和学习所需的感觉输入之间的联系也应该依赖于通过这些受体发出信号的准确时间和大小。阻滞素的一个主要功能是下调激活的GPCRs，这表明这些蛋白质是感觉处理和联系过程的基础。本研究的目的是了解果蝇神经系统中Kurtz非视觉arrestin的功能，从而确定激动剂诱导的G蛋白偶联受体脱敏在行为中的重要性。这项拟议的研究将利用Kurtz arrestin的突变体和新产生的转基因来研究Kurtz arrestin在感觉加工以及在负强化的联想和操作条件反射学习范式中的功能。具体地说，这些实验将提出这样一个问题：激活的GPCRs的快速脱敏和再敏化是否是准确的嗅觉处理以及学习和记忆过程中的必需条件。其他实验将表征库尔茨arrestin的生化和细胞特性。这些结果可能允许在行为表型和与特定GPCR的相互作用之间得出特定的相关性。如果激动剂诱导的GPCRs脱敏确实对准确计时神经元输入以最大限度地提高信息联系至关重要，那么阻滞剂可能成为认知增强剂的有吸引力的靶点，最终可能有助于治疗与衰老相关的记忆衰退以及包括阿尔茨海默病在内的认知障碍。

DESCRIPTION (provided by applicant): Much of the information animals receive from the environment is gathered through G protein-coupled receptors (GPCRs). The ability to attenuate the signaling of these receptors would be most desirable in order to have an accurate perception of the environment. Additionally, the association between sensory inputs required for synaptic plasticity and learning should also be dependent on the precise timing and magnitude of signaling through these receptors. A primary function of arrestins, to down regulate activated GPCRs, suggests that these proteins are fundamental to the processes of sensory processing and association. The objective of the proposed research is to understand the function of the kurtz non-visual arrestin within the nervous system of Drosophila, and thereby determine the importance of agonist-induced desensitization of G protein-coupled receptors in behavior. The proposed studies will utilize mutants of the kurtz arrestin and newly generated transgenes to examine the function of the kurtz arrestin in sensory processing, and in both negatively-reinforced associative and operant conditioning learning paradigms. Specifically, the experiments will ask the question of whether the rapid desensitization and the resensitization of activated GPCRs is a requirement for accurate olfactory processing and in the processes of learning and memory. Additional experiments will characterize the biochemical and cellular properties of the kurtz arrestin. These results may allow for specific correlations to be drawn between behavioral phenotypes and the interactions with a specific GPCR. If agonist-induced desensitization of GPCRs is indeed critical to accurately time neuronal inputs so as to maximize informative associations, then arrestins may become attractive targets for cognitive enhancers that may eventually help treat aging associated memory decline as well as cognitive disorders including Alzheimer's disease.