Regulation of DARPP-32 dephosphorylation at PKA- and Cdk5-sites by NMDA and AMPA receptors: distinct roles of calcineurin and protein phosphatase-2A
Regulation of DARPP-32 dephosphorylation at PKA- and Cdk5-sites by NMDA and AMPA receptors: distinct roles of calcineurin and protein phosphatase-2A
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DOI：
10.1046/j.1471-4159.2002.00876.x
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发表时间：
2002-05-01
影响因子：
4.7
通讯作者：
Greengard, P
中科院分区：
文献类型：
--
作者：
Nishi, A;Bibb, JA;Greengard, P
来自皮质纹状体和丘脑纹状体通路的谷氨酸能输入已被证明调节新纹状体神经元中的多巴胺能信号传导。DARPP-32（M-r 32 kDa的多巴胺和cAMP调节的磷蛋白）是一种信号转导分子，可调节新纹状体神经元中多巴胺信号传导的功效。多巴胺信号传导部分地通过cAMP依赖性蛋白激酶在Thr 34处对DARPP-32的磷酸化来介导，并且通过细胞周期蛋白依赖性蛋白激酶5在Thr 75处对DARPP-32的磷酸化来拮抗。我们现在已经研究了离子型谷氨酸NMDA和AMPA受体对新纹状体切片中DARPP-32磷酸化的影响。NMDA和AMPA受体的激活降低了DARPP-32在Thr 34和Thr 75处的磷酸化状态。Thr 34磷酸化的减少通过Ca 2+依赖性激活Ca 2 +/钙调蛋白依赖性磷酸酶钙调磷酸酶介导。相反，Thr 75磷酸化的减少是通过蛋白磷酸酶-2A介导的钙依赖性去磷酸化激活。这些结果为谷氨酸通过不同蛋白磷酸酶调节DARPP-32不同位点的去磷酸化对多巴胺能信号传导的复杂作用提供了支持。
Glutamatergic inputs from corticostriatal and thalamostriatal pathways have been shown to modulate dopaminergic signaling in neostriatal neurons. DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of M-r 32 kDa) is a signal transduction molecule that regulates the efficacy of dopamine signaling in neostriatal neurons. Dopamine signaling is mediated in part through phosphorylation of DARPP-32 at Thr34 by cAMP-dependent protein kinase, and antagonized by phosphorylation of DARPP-32 at Thr75 by cyclin-dependent protein kinase 5. We have now investigated the effects of the ionotropic glutamate NMDA and AMPA receptors on DARPP-32 phosphorylation in neostriatal slices. Activation of NMDA and AMPA receptors decreased the state of phosphorylation of DARPP-32 at Thr34 and Thr75. The decrease in Thr34 phosphorylation was mediated through Ca2+-dependent activation of the Ca2+ -/calmodulin-dependent phosphatase, calcineurin. In contrast, the decrease in Thr75 phosphorylation was mediated through Ca2+-dependent activation of dephosphorylation by protein phosphatase-2A. The results provide support for a complex effect of glutamate on dopaminergic signaling through the regulation of dephosphorylation of different sites of DARPP-32 by different protein phosphatases.