A phosphatase cascade by which rewarding stimuli control nucleosomal response.
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.
Stipanovich
Alexandre
A
Inserm, UMR-S 839, 75005 Paris, France.
Valjent
Emmanuel
E
Matamales
Miriam
M
Nishi
Akinori
A
Ahn
Jung-Hyuck
JH
Maroteaux
Matthieu
M
Bertran-Gonzalez
Jesus
J
Brami-Cherrier
Karen
K
Enslen
Hervé
H
Corbillé
Anne-Gaëlle
AG
Filhol
Odile
O
Nairn
Angus C
AC
Greengard
Paul
P
Hervé
Denis
D
Girault
Jean-Antoine
JA
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
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