The Function of Arrestin in Drosophila Behavior

描述（由申请人提供）：动物从环境中接收的大部分信息是通过G蛋白偶联受体（gpcr）收集的。为了对环境有一个准确的感知，减弱这些受体信号的能力将是最可取的。此外，突触可塑性和学习所需的感觉输入之间的关联也应该取决于通过这些受体的信号传导的精确时间和强度。抑制蛋白的主要功能是下调激活的gpcr，这表明这些蛋白是感觉加工和联想过程的基础。本研究的目的是了解果蝇神经系统中kurtz非视觉抑制蛋白的功能，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。这些研究将利用kurtz阻滞蛋白的突变体和新产生的转基因来检验kurtz阻滞蛋白在感觉加工中的功能，以及在负强化联想和操作性条件反射学习范式中的功能。具体而言，实验将提出激活gpcr的快速脱敏和再敏是否是准确嗅觉加工和学习记忆过程的要求。进一步的实验将表征库尔兹阻滞的生化和细胞特性。这些结果可能允许在行为表型和与特定GPCR的相互作用之间绘制特定的相关性。如果激动剂诱导的gpcr脱敏确实对准确地确定神经元输入的时间以最大化信息关联至关重要，那么抑制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.