title: A phosphatase cascade by which rewarding stimuli control nucleosomal response.
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.
authors.affiliation: Inserm, UMR-S 839, 75005 Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Stipanovich
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Valjent
authors.forename: Miriam
authors.initials: M
authors.lastname: Matamales
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
authors.forename: Jung-Hyuck
authors.initials: JH
authors.lastname: Ahn
authors.forename: Matthieu
authors.initials: M
authors.lastname: Maroteaux
authors.forename: Jesus
authors.initials: J
authors.lastname: Bertran-Gonzalez
authors.forename: Karen
authors.initials: K
authors.lastname: Brami-Cherrier
authors.forename: Hervé
authors.initials: H
authors.lastname: Enslen
authors.forename: Anne-Gaëlle
authors.initials: AG
authors.lastname: Corbillé
authors.forename: Odile
authors.initials: O
authors.lastname: Filhol
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Denis
authors.initials: D
authors.lastname: Hervé
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Girault
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005502:Food; D006657:Histones / Q000378:metabolism; D007858:Learning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009042:Motivation; D009043:Motor Activity / Q000502:physiology; D017072:Neostriatum / Q000166:cytology; D009474:Neurons / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects; D019966:Substance-Related Disorders
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D006657:Histones; D009707:Nucleosomes; C497929:Ppp1r1b protein, mouse; C497930:Ppp1r1b protein, rat; D010768:Phosphoserine; D010749:Phosphoprotein Phosphatases; D004298:Dopamine