A phosphatase cascade by which rewarding stimuli control nucleosomal response

作者：Stipanovich Alexandre; Valjent Emmanuel; Matamales Miriam; Nishi Akinori; Ahn Jung Hyuck; Maroteaux Matthieu; Bertran Gonzalez Jesus; Brami Cherrier Karen; Enslen Herve; Corbille Anne Gaelle; Filhol Odile; Nairn Angus C; Greengard Paul; Herve Denis; Girault Jean Antoine^*

来源：Nature, 2008, 453(7197): 879-U23.

DOI：10.1038/nature06994

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.

• 出版日期2008-6-12
• 单位中国地震局