A phosphatase cascade by which rewarding stimuli control nucleosomal response
A phosphatase cascade by which rewarding stimuli control nucleosomal response
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DOI：
10.1038/nature06994
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发表时间：
2008-06-12
期刊：
影响因子：
64.8
通讯作者：
Girault, Jean-Antoine
中科院分区：
文献类型：
--
作者：
Stipanovich, Alexandre;Valjent, Emmanuel;Girault, Jean-Antoine
多巴胺协调运动行为和奖励驱动的学习。多巴胺信号的紊乱与几种神经和精神疾病有关，也与药物成瘾有关。多巴胺的作用在一定程度上是通过调节纹状体中的基因表达来实现的，其机制尚不完全清楚。在这里，我们表明，滥用药物，以及食物强化学习，促进了32 kDa多巴胺调节和环磷酸腺苷调节的磷酸蛋白(DARPP-32)的核积累。这种聚集是通过涉及多巴胺D1受体的信号级联反应、cAMP依赖的蛋白磷酸酶-2A的激活、DARPP-32在Ser97的去磷酸化以及其核输出的抑制来调节的。DARPP-32是一种有效的蛋白磷酸酶-1抑制剂，它的核积累增加了组蛋白H3的磷酸化，组蛋白H3是核小体反应的重要组成部分。Ser97的突变深刻地改变了滥用药物的行为影响，降低了对食物的动力，强调了这一信号级联反应的功能重要性。
Dopamine orchestrates motor behaviour and reward- driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32- kDa dopamine- regulated and cyclic- AMP- regulated phosphoprotein ( DARPP- 32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP- dependent activation of protein phosphatase- 2A, dephosphorylation of DARPP- 32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP- 32, a potent inhibitor of protein phosphatase- 1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade.