Amplification of dopaminergic signaling by a positive feedback loop
Amplification of dopaminergic signaling by a positive feedback loop
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DOI：
10.1073/pnas.220410397
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发表时间：
2000-11-07
影响因子：
11.1
通讯作者：
Greengard, P
中科院分区：
文献类型：
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作者：
Nishi, A;Bibb, JA;Greengard, P
多巴胺和 M-r 32,000 的 cAMP 调节磷蛋白 (DARPP-32) 在多巴胺的大部分作用中发挥着重要作用。在静息新纹状体切片中，细胞周期蛋白依赖性激酶 5 (Cdk5) 磷酸化 DARPP-32 Thr-75。从而降低多巴胺能信号传导的功效。我们在这里报告，切片中的多巴胺和整个动物中的急性可卡因降低了纹状体 DARPP-32 Thr-75 的磷酸化状态，从而消除了这种抑制限制。多巴胺的这种作用是通过多巴胺 D1 受体介导的 cAMP 依赖性蛋白激酶 (PKA) 激活来实现的。激活的 PKA 通过降低 DARPP-32-Thr-75 的磷酸化状态来解除自身抑制。多巴胺 D2 受体刺激具有相反的效果。活化的 PKA 降低 DARPP-32-Thr-75 磷酸化状态的能力显然可归因于蛋白磷酸酶-2A 活性的增加，而 Cdk5 不受影响。总之，这些结果表明，通过正反馈机制，Cdk5 信号传导和 PKA 信号传导是相互拮抗的。
Dopamine and cAMP-regulated phosphoprotein of M-r 32,000 (DARPP-32) plays an obligatory role in most of the actions of dopamine. in resting neostriatal slices, cyclin-dependent kinase 5 (Cdk5) phosphorylates DARPP-32 at Thr-75. thereby reducing the efficacy of dopaminergic signaling. We report here that dopamine, in slices, and acute cocaine, in whole animals, decreases the state of phosphorylation of striatal DARPP-32 at Thr-75 and thereby removes this inhibitory constraint. This effect of dopamine is achieved through dopamine D1 receptor-mediated activation of cAMP-dependent protein kinase (PKA). The activated PKA, by decreasing the state of phosphorylation of DARPP-32-Thr-75, deinhibits itself. Dopamine D2 receptor stimulation has the opposite effect. The ability of activated PKA to reduce the state of phosphorylation of DARPP-32-Thr-75 is apparently attributable to increased protein phosphatase-2A activity, with Cdk5 being unaffected. Together, these results indicate that via positive feedback mechanisms, Cdk5 signaling and PKA signaling are mutually antagonistic.