A novel mechanism by which dopamine alters chromatin in neurons
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 A*, Valjent E*, Matamales M*, Nishi A, Ahn JH, Maroteaux M, Bertran-Gonzalez J, Brami-Cherrier K, Enslen H, Corbillé AG, Filhol O, Nairn AC, Greengard P, Hervé D, Girault JA (2008) A phosphatase cascade by which rewarding stimuli control nucleosomal response. Nature 453 (7197), 879-884. [Journal Article]
Research Highlight, Hoyos Flight M (2008) Rewarding changes in gene expression Nature Reviews Neuroscience 9, 499. [Journal Article]
Other articles related to this work:
Nishi A, Matamales M, Musante V, Valjent E, Kuroiwa M, Kitahara Y, Rebholz H, Greengard P, Girault JA, Nairn AC (2017) Glutamate counteracts dopamine/PKA signaling via dephosphorylation of DARPP-32 Ser-97 and alteration of its cytonuclear distribution. Journal of Biological Chemistry 292 (4), 1462-1476. [Journal Article]
Matamales M (2012) Neuronal activity-regulated gene transcription: how are distant synaptic signals conveyed to the nucleus? F1000Research 1: 69. [Journal Article]
Matamales, Girault JA (2011) Signaling from the cytoplasm to the nucleus in striatal medium-sized spiny neurons. Frontiers in Neuroanatomy 5. [Journal Article]
GRANT FUNDING
Our work is currently supported by the Australian Research Council, the National Health and Medical Research Council, the Tourette Association of America and UNSW. Click for details
RESEARCH ETHICS & SAFETY
All experimental procedures are approved by the Animal Care and Ethics Commitee and the Gene Technology Research Commitee at UNSW.
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