Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
J Biol Chem. 2012 Aug 10;287(33):27806-12. doi: 10.1074/jbc.M112.388413. Epub 2012 Jun 29.
Dyskinesia, a motor complication caused by prolonged administration of the antiparkinsonian drug l-3,4-dihydroxyphenylalanine (l-DOPA), is accompanied by activation of cAMP signaling and hyperphosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). Here, we show that the abnormal phosphorylation of DARPP-32 occurs specifically in medium spiny neurons (MSNs) expressing dopamine D1 receptors (D1R). Using mice in which DARPP-32 is selectively deleted in D1R-expressing MSNs, we demonstrate that this protein is required for l-DOPA-induced activation of the extracellular signal-regulated protein kinases 1 and 2 and the mammalian target of rapamycin complex 1 (mTORC1) pathways, which are implicated in dyskinesia. We also show that mutation of the phosphorylation site for cAMP-dependent protein kinase on DARPP-32 attenuates l-DOPA-induced dyskinesia and reduces the concomitant activations of ERK and mTORC1 signaling. These studies demonstrate that, in D1R-expressing MSNs, l-DOPA-induced activation of ERK and mTORC1 requires DARPP-32 and indicates the importance of the cAMP/DARPP-32 signaling cascade in dyskinesia.
运动障碍，一种由抗帕金森病药物左旋多巴（l-DOPA）长期给药引起的运动并发症，伴随着环腺苷酸（cAMP）信号的激活和多巴胺和 cAMP 调节的 32 kDa 磷酸蛋白（DARPP-32）的过度磷酸化。在这里，我们表明 DARPP-32 的异常磷酸化特异性发生在表达多巴胺 D1 受体（D1R）的中型多棘神经元（MSNs）中。使用 DARPP-32 在表达 D1R 的 MSNs 中选择性缺失的小鼠，我们证明该蛋白对于 l-DOPA 诱导的细胞外信号调节蛋白激酶 1 和 2 和雷帕霉素靶蛋白复合物 1（mTORC1）途径的激活是必需的，这些途径与运动障碍有关。我们还表明，DARPP-32 上的 cAMP 依赖性蛋白激酶磷酸化位点的突变可减轻 l-DOPA 诱导的运动障碍，并降低 ERK 和 mTORC1 信号的伴随激活。这些研究表明，在表达 D1R 的 MSNs 中，l-DOPA 诱导的 ERK 和 mTORC1 的激活需要 DARPP-32，并表明 cAMP/DARPP-32 信号级联在运动障碍中的重要性。
