β-arrestin2 alleviates L-dopa–induced dyskinesia via lower D1R activity in Parkinson’s rats
β-arrestin2 alleviates L-dopa–induced dyskinesia via lower D1R activity in Parkinson’s rats
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DOI：
10.18632/aging.102574
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发表时间：
2019-12
期刊：
影响因子：
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通讯作者：
Xing-Ru Zhang;Zengrui Zhang;Siyan Chen;Wen-wen Wang;Xin-Shi Wang;Jin-Cai He;Cheng-Long Xie
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文献类型：
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作者：
Xing-Ru Zhang;Zengrui Zhang;Siyan Chen;Wen-wen Wang;Xin-Shi Wang;Jin-Cai He;Cheng-Long Xie
L多巴诱发的运动障碍(LID)的原因被归因于G蛋白偶联受体(GPCRs)的超敏和下游信号的失控。目前认为β-arrestin2通过其支架作用于多种细胞内分子来影响gpr信号转导。我们利用重组腺相关病毒载体过表达和消融β-arrestin2。用Western印迹和免疫组织化学方法检测L多巴对纹状体信号分子和其他蛋白表达的影响。我们的数据表明，通过腺病毒介导的β-arrestin2的过表达，在6-羟基多巴胺损伤的啮齿动物模型中，LID的表现减弱。β-arrestin2抑制LID行为，而不影响L-多巴的抗帕金森病作用。此外，我们还发现D1R激动剂SKF38393逆转了β-arrestin2的抗运动障碍作用。相反，大鼠基因敲除研究表明，β-arrestin2的可用性降低会降低LID的性能，这一作用可被D1R拮抗剂SCH23390所抵消。这些数据不仅显示了β-arrestin2/GPCR2信号在LID中的中心作用，而且还显示了D1R信号通路在多巴胺能去神经和脉冲性给药L-多巴的反应中发生的变化。
The cause of the L-dopa–induced dyskinesia (LID) has been ascribed to G-protein coupled receptor (GPCR) supersensitivity and uncontrolled downstream signaling. It is now supposed that β-arrestin2 affects GPCR signaling through its ability to scaffold various intracellular molecules. We used the rAAV (recombinant adeno-associated virus) vectors to overexpress and ablation of β-arrestin2. L-dopa-induced changes in expression of signaling molecules and other proteins in the striatum were examined by western blot and immunohistochemically. Our data demonstrated that via AAV-mediated overexpression of β-arrestin2 attenuated LID performance in 6-OHDA-lesioned rodent models. β-arrestin2 suppressed LID behavior without compromising the antiparkinsonian effects of L-dopa. Moreover, we also found that the anti-dyskinetic effect of β-arrestin2 was reversed by SKF38393, a D1R agonist. On the contrary, the rat knockdown study demonstrated that reduced availability of β-arrestin2 deteriorated LID performance, which was counteracted by SCH23390, a D1R antagonist. These data not only demonstrate a central role for β-arrestin2/GPCR signaling in LID, but also show the D1R signal pathway changes occurring in response to dopaminergic denervation and pulsatile administration of L-dopa.