A phosphatase cascade by which rewarding stimuli control nucleosomal response

Alexandre Stipanovich, Emmanuel Valjent, Miriam Matamales, Akinori Nishi, Jung Hyuck Ahn, Matthieu Maroteaux, Jesus Bertran-Gonzalez, Karen Brami-Cherrier, Hervé Enslen, Anne Gaëlle Corbillé, Odile Filhol, Angus C. Nairn, Paul Greengard, Denis Hervé, Jean Antoine Girault

Research output: Contribution to journalArticlepeer-review

193 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)879-884
Number of pages6
JournalNature
Volume453
Issue number7197
DOIs
StatePublished - 12 Jun 2008

Bibliographical note

Funding Information:
Acknowledgements We thank M. Lambert for her help with time-lapse video; P. Ingrassia and P. Bernard for their help with mutant mice; and M. R. Picciotto, S. Cottecchia, J. P. Hornung, R. Luedtke, M. Takeda and Intracellular Therapies Inc. for reagents. This work was supported by Inserm, and by grants from Agence Nationale de la Recherche (05-NEUR-020-01), Fondation Bettencourt-Schueller (Coup d’élan) and Association pour la Recherche contre le Cancer (ARC-3118 and -7905) to J.A.G., from Fondation pour la Recherche Médicale (FRM) to D.H., a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science to A.N., and grants from the National Institute on Drug Abuse (DA10044), the National Institute of Mental Health (MH74866), the US Department of Defense (W81XWH-05-1-0146), the Picower Foundation, the Michael Stern Parkinson’s Research Foundation and the US Army Medical Research Acquisition Activity (DAMD17-02-1-0705 and W81XWH-05-1-0146) to P.G. and A.C.N. A.S. was supported by Mission Interministérielle de Lutte contre la Drogue et la Toxicomanie and FRM, and J.B.G. by FRM.

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