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

项目摘要/摘要 本提案旨在阐明孤儿G蛋白偶联受体GPR88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非常有兴趣，但仍然很差 在细胞机制的水平上被理解。该项目以详细的解剖结构开始(具体目标1) GPR88在大脑和整个发育过程中表达的形态特征，建立在 初步研究表明，GPR88是受发育调节的，并且不同地针对或 在不同的神经元群体中排除在初级纤毛之外。然后重点描述了其机制基础 GPR88选择性靶向神经元纤毛(特定目标2)，并确定GPR88是如何调节的 相关纹状体神经元中的信号以及睫状体受体定位或排斥如何改变这一功能 (具体目标3)。建议的研究建立在GPR88药理和信号转导的最新进展基础上 生物传感器工具开发。这些研究试图提供第一个直接的证据来证明 GPR88在天然受体表达水平上的神经调节，定义了GPR88的功能后果 定位于神经元的初级纤毛，并有助于描绘一个了解功能的框架。 初级纤毛在更广泛的GPCR介导的神经调节中的后果(S)。

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.