Massart Renaud, Guilloux Jean-Philippe, Mignon Virginie, Sokoloff Pierre, Diaz Jorge
INSERM U-573, Neurobiologie et Pharmacologie Moléculaire, Paris, France.
Eur J Neurosci. 2009 Aug;30(3):397-414. doi: 10.1111/j.1460-9568.2009.06842.x. Epub 2009 Jul 28.
GPR88, an orphan G protein-coupled receptor, was designated Strg/GPR88 for striatum-specific G protein-coupled receptor (K. Mizushima et al. (2000)Genomics, 69, 314-321). In this study, we focused on striatal GPR88 protein localization using a polyclonal antibody. We established that the distribution of immunoreactivity in rat brain matched that of GPR88 transcripts and provided evidence for its exclusive neuronal expression. GPR88 protein is abundant throughout the striatum of rat and primate, with expression limited to the two subsets of striatal projection medium spiny neurons (MSNs) expressing preprotachykinin-substance P or preproenkephalin mRNAs. Ultrastructural immunolabelling revealed the GPR88 concentration at post-synaptic sites along the somatodendritic compartments of MSNs, with pronounced preference for dendrites and dendritic spines. The GPR88-rich expression, in both striatal output pathways, designates this receptor as a potential therapeutic target for diseases involving dysfunction of the basal ganglia, such as Parkinson's disease. Hence, we investigated changes of GPR88 expression in a model of Parkinson's disease (unilateral 6-hydroxydopamine-lesioned rats) following repeated L-DOPA treatment. In dopamine-depleted striatum, GPR88 expression was differentially regulated, i.e. decreased in striatopallidal and increased in striatonigral MSNs. L-DOPA treatment led to a normalization of GPR88 levels through dopamine D1 and D2 receptor-mediated mechanisms in striatopallidal and striatonigral MSNs, respectively. Moreover, the removal of corticostriatal inputs, by ibotenate infusion, downregulated GPR88 in striatopallidal MSNs. These findings provide the first evidence that GPR88 is confined to striatal MSNs and indicate that L-DOPA-mediated behavioural effects in hemiparkinsonian rats may involve normalization of striatal GPR88 levels probably through dopamine receptor-mediated mechanisms and modulations of corticostriatal pathway activity.
GPR88是一种孤儿G蛋白偶联受体，被命名为Strg/GPR88，即纹状体特异性G蛋白偶联受体（K. 水岛等人（2000年）《基因组学》，69卷，314 - 321页）。在本研究中，我们使用多克隆抗体聚焦于纹状体GPR88蛋白的定位。我们确定大鼠脑中免疫反应性的分布与GPR88转录本的分布相匹配，并为其仅在神经元中表达提供了证据。GPR88蛋白在大鼠和灵长类动物的整个纹状体中含量丰富，其表达仅限于表达前速激肽 - P物质或前脑啡肽原mRNA的纹状体投射中型多棘神经元（MSNs）的两个亚群。超微结构免疫标记显示GPR88集中在MSNs体树突区的突触后位点，对树突和树突棘有明显偏好。在两种纹状体输出通路中GPR88的丰富表达表明该受体是涉及基底神经节功能障碍的疾病（如帕金森病）的潜在治疗靶点。因此，我们研究了帕金森病模型（单侧6 - 羟基多巴胺损伤大鼠）在反复左旋多巴治疗后GPR88表达的变化。在多巴胺耗竭的纹状体中，GPR88表达受到不同调节，即在纹状体苍白球通路中降低，而在纹状体黑质通路的MSNs中升高。左旋多巴治疗分别通过多巴胺D1和D2受体介导的机制使纹状体苍白球和纹状体黑质通路的MSNs中GPR88水平恢复正常。此外，通过注入鹅膏蕈氨酸去除皮质纹状体输入，可下调纹状体苍白球通路MSNs中的GPR88。这些发现首次证明GPR88局限于纹状体MSNs，并表明左旋多巴在偏侧帕金森病大鼠中介导的行为效应可能涉及纹状体GPR88水平的恢复正常，这可能是通过多巴胺受体介导的机制以及皮质纹状体通路活性的调节实现的。
