Regulation of DARPP-32 phosphorylation by three distinct dopamine D1-like receptor signaling pathways in the neostriatum
Regulation of DARPP-32 phosphorylation by three distinct dopamine D1-like receptor signaling pathways in the neostriatum
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DOI：
10.1111/j.1471-4159.2008.05702.x
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发表时间：
2008-11-01
影响因子：
4.7
通讯作者：
Nishi, Akinori
中科院分区：
文献类型：
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作者：
Kuroiwa, Mahomi;Bateup, Helen S.;Nishi, Akinori
多巴胺D-1样受体在多巴胺能信号传导中起关键作用。除了G（s/olf）/腺苷酸环化酶（AC）偶联的D-1受体之外，已经提出存在与G（q）/磷脂酶C（PLC）偶联的D-1样受体。已知苯并氮杂卓D-1受体激动剂差异地激活G（s/olf）/AC和G（q）/PLC信号传导。通过利用SKF 83959和SKF 83822，我们研究了D-1样受体信号转导级联，其调节小鼠新纹状体切片中Thr 34（PKA位点）的DARPP-32磷酸化。用SKF 83959或SKF 83822处理增加DARPP-32磷酸化。SKF 83959和SKF 83822诱导的DARPP-32磷酸化的增加在很大程度上但部分地被D-1受体拮抗剂SCH 23390拮抗，并且剩余的SCH 23390不敏感的增加被腺苷A（2A）受体拮抗剂消除。此外，SKF 83959诱导的SCH 23390敏感性DARPP-32磷酸化增加被PLC抑制剂增强。对D1 R/D2 R-DARPP-32小鼠切片的分析显示，两种D-1受体激动剂均调节纹状体黑质神经元中的DARPP-32磷酸化，但不调节纹状体苍白球神经元中的DARPP-32磷酸化。因此，多巴胺D-1样受体与纹状体黑质神经元中的三个信号级联反应偶联：（i）SCH 23390敏感性G（s/olf）/AC/PKA，（ii）腺苷A（2A）受体依赖性G（s/olf）/AC/PKA，和（iii）G（q）/PLC信号。有趣的是，G（q）/PLC信号与SCH 23390敏感的G（s/olf）/AC/PKA信号相互作用，导致其抑制。由D-1样受体激活的三个信号级联可能在多巴胺能调节精神功能中发挥独特的作用。
Dopamine D-1-like receptors play a key role in dopaminergic signaling. In addition to G(s/olf)/adenylyl cyclase (AC)-coupled D-1 receptors, the presence of D-1-like receptors coupled to G(q)/phospholipase C (PLC) has been proposed. Benzazepine D-1 receptor agonists are known to differentially activate G(s/olf)/AC and G(q)/PLC signaling. By utilizing SKF83959 and SKF83822, we investigated the D-1-like receptor signaling cascades, which regulate DARPP-32 phosphorylation at Thr34 (the PKA-site) in mouse neostriatal slices. Treatment with SKF83959 or SKF83822 increased DARPP-32 phosphorylation. The SKF83959- and SKF83822-induced increase in DARPP-32 phosphorylation was largely, but partially, antagonized by a D-1 receptor antagonist, SCH23390, and the residual SCH23390-insensitive increase was abolished by an adenosine A(2A) receptor antagonist. In addition, the SKF83959-induced, SCH23390-sensitive increase in DARPP-32 phosphorylation was enhanced by a PLC inhibitor. Analysis in slices from D1R/D2R-DARPP-32 mice revealed that both D-1 receptor agonists regulate DARPP-32 phosphorylation in striatonigral, but not in striatopallidal, neurons. Thus, dopamine D-1-like receptors are coupled to three signaling cascades in striatonigral neurons: (i) SCH23390-sensitive G(s/olf)/AC/PKA, (ii) adenosine A(2A) receptor-dependent G(s/olf)/AC/PKA, and (iii) G(q)/PLC signaling. Interestingly, G(q)/PLC signaling interacts with SCH23390-sensitive G(s/olf)/AC/PKA signaling, resulting in its inhibition. Three signaling cascades activated by D-1-like receptors likely play a distinct role in dopaminergic regulation of psychomotor functions.