Striatal GPR88 expression is confined to the whole projection neuron population and is regulated by dopaminergic and glutamatergic afferents
Striatal GPR88 expression is confined to the whole projection neuron population and is regulated by dopaminergic and glutamatergic afferents
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DOI：
10.1111/j.1460-9568.2009.06842.x
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发表时间：
2009-08-01
影响因子：
3.4
通讯作者：
Diaz, Jorge
中科院分区：
文献类型：
--
作者：
Massart, Renaud;Guilloux, Jean-Philippe;Diaz, Jorge
GPR88，一种孤儿G蛋白偶联受体，被命名为Strg/GPR88，表示纹状体特异性G蛋白偶联受体(K.Mizushima等人(2000)Genomics，69, 314-321)。在本研究中，我们重点使用多克隆抗体进行纹状体 GPR88 蛋白定位。我们确定大鼠大脑中免疫反应性的分布与 GPR88 转录物的分布相匹配，并为其独特的神经元表达提供了证据。 GPR88 蛋白在大鼠和灵长类动物的纹状体中含量丰富，表达仅限于表达前原速激肽 P 物质或前脑啡肽原 mRNA 的纹状体投射中型多棘神经元 (MSN) 的两个亚群。超微结构免疫标记揭示了 MSN 体细胞树突区突触后位点的 GPR88 浓度，并且明显偏爱树突和树突棘。在两条纹状体输出途径中，GPR88 丰富的表达表明该受体作为涉及基底神经节功能障碍的疾病（例如帕金森病）的潜在治疗靶点。因此，我们研究了重复左旋多巴治疗后帕金森病模型（单侧 6-羟基多巴胺损伤的大鼠）中 GPR88 表达的变化。在多巴胺耗尽的纹状体中，GPR88 表达受到差异性调节，即纹状体苍白球中减少，纹状体黑质 MSN 中增加。 L-DOPA 治疗分别通过纹状体苍白球和纹状体黑质 MSN 中多巴胺 D1 和 D2 受体介导的机制导致 GPR88 水平正常化。此外，通过输注鹅膏酯去除皮质纹状体输入，可下调纹状体苍白球 MSN 中的 GPR88。这些发现提供了第一个证据，表明 GPR88 仅限于纹状体 MSN，并表明左旋多巴介导的偏侧帕金森病大鼠的行为效应可能涉及纹状体 GPR88 水平的正常化，可能通过多巴胺受体介导的机制和皮质纹状体通路活性的调节。
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.