GPR88 localization to primary cilia and its impact on striatal cAMP signaling

项目总结/摘要 本研究旨在阐明GPR 88（一种孤儿G蛋白偶联受体）的基本细胞神经生物学 （GPCR）作为神经精神疾病的潜在治疗靶点具有很大的兴趣，但仍然很差 在细胞机制的水平上理解。该项目开始（具体目标1）与详细的解剖 GPR 88在脑和跨发育中表达的形态学表征， 初步研究表明，GPR 88是发育调节的，并且差异靶向或 在不同的神经元群体中从初级纤毛中排除。然后，它侧重于描绘的机制基础 选择性靶向GPR 88至神经元纤毛（特异性目标2），并确定GPR 88如何调节 相关纹状体神经元中的信号传导以及睫状受体定位或排除如何改变该功能 （具体目标3）。这项研究建立在GPR 88药理学和信号传导的最新进展基础上。 生物传感器工具开发。这些研究试图提供关于以下影响的第一个直接证据： GPR 88在天然受体表达水平上对神经调节的作用，定义GPR 88的功能后果 定位到神经元的初级纤毛，并帮助描绘一个框架，以了解功能 更一般地，初级纤毛在GPCR介导的神经调节中的后果。

PROJECT SUMMARY / ABSTRACT This proposal seeks to elucidate the basic cellular neurobiology of GPR88, an orphan G protein-coupled receptor (GPCR) that is of great interest as a potential therapeutic target for neuropsychiatric disease but remains poorly understood at the level of cellular mechanism. The project begins (Specific Aim 1) with a detailed anatomical and morphological characterization of GPR88 expression in brain and across development, building on preliminary studies indicating that GPR88 is developmentally regulated and is differentially targeted to or excluded from primary cilia in distinct neuronal populations. It then focuses on delineating the mechanistic basis of selective targeting of GPR88 to neuronal cilia (Specific Aim 2), and determining how GPR88 modulates signaling in relevant striatal neurons and how ciliary receptor localization or exclusion changes this function (Specific Aim 3). The proposed studies build on recent advances in GPR88 pharmacology and signaling biosensor tool development. These studies seek to provide the first direct evidence regarding the effects of GPR88 on neuromodulation at native receptor expression levels, define functional consequences of GPR88 localization to primary cilia of neurons, and help delineate a framework for understanding the functional consequence(s) of primary cilia in GPCR-mediated neuromodulation more generally.