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.
GPR88 is an orphan GPCR that critically modulates dopamine-dependent behaviors and is an attractive therapeutic target for the treatment of neuropsychiatric illnesses. Cellular functions of GPR88 remain poorly understood, and GPR88 is unusual among GPCRs because localizes specifically to the primary cilium of some neurons. The proposed studies apply newly developed tools to elucidate GPR88 signaling in such neurons, with particular emphasis on determining the significance of GPR88 localization to cilia. These studies will fundamentally advance the neurobiology of GPR88 and primary cilia, and may identify novel strategies or targets useful for therapeutic manipulation of striatal dysfunctions that underlie important neuropsychiatric pathologies.
