Histone H3 phosphorylation is under the opposite tonic control of dopamine D2 and adenosine A2A receptors in striatopallidal neurons

Bertran-Gonzalez, Jesus, Håkansson, Kerstin, Borgkvist, Anders, Irinopoulou, Theano, Brami-Cherrier, Karen, Usiello, Alessandro, Greengard, Paul, Hervé, Denis, Girault, Jean-Antoine, Valjent, Emmanuel and Fisone, Gilberto (2009) Histone H3 phosphorylation is under the opposite tonic control of dopamine D2 and adenosine A2A receptors in striatopallidal neurons. Neuropsychopharmacology, 34 7: 1710-1720. doi:10.1038/npp.2008.228


Author Bertran-Gonzalez, Jesus
Håkansson, Kerstin
Borgkvist, Anders
Irinopoulou, Theano
Brami-Cherrier, Karen
Usiello, Alessandro
Greengard, Paul
Hervé, Denis
Girault, Jean-Antoine
Valjent, Emmanuel
Fisone, Gilberto
Title Histone H3 phosphorylation is under the opposite tonic control of dopamine D2 and adenosine A2A receptors in striatopallidal neurons
Journal name Neuropsychopharmacology   Check publisher's open access policy
ISSN 0893-133X
1740-634X
Publication date 2009
Sub-type Article (original research)
DOI 10.1038/npp.2008.228
Open Access Status
Volume 34
Issue 7
Start page 1710
End page 1720
Total pages 11
Place of publication London United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted abstract
The antipsychotic agent haloperidol regulates gene transcription in striatal medium spiny neurons (MSNs) by blocking dopamine D2 receptors (D2Rs). We examined the mechanisms by which haloperidol increases the phosphorylation of histone H3, a key step in the nucleosomal response. Using bacterial artificial chromosome (BAC)-transgenic mice that express EGFP under the control of the promoter of the dopamine D1 receptor (D1R) or the D2R, we found that haloperidol induced a rapid and sustained increase in the phosphorylation of histone H3 in the striatopallidal MSNs of the dorsal striatum, with no change in its acetylation. This effect was mimicked by raclopride, a selective D2R antagonist, and prevented by the blockade of adenosine A2A receptors (A2ARs), or genetic attenuation of the A2AR-associated G protein, Gαolf. Mutation of the cAMP-dependent phosphorylation site (Thr34) of the 32-kDa dopamine and cAMP-regulated phosphoprotein (DARPP-32) decreased the haloperidol-induced H3 phosphorylation, supporting the role of cAMP in H3 phosphorylation. Haloperidol also induced extracellular signal-regulated kinase (ERK) phosphorylation in striatopallidal MSNs, but this effect was not implicated in H3 phosphorylation. The levels of mitogen- and stress-activated kinase 1 (MSK1), which has been reported to mediate ERK-induced H3 phosphorylation, were lower in striatopallidal than in striatonigral MSNs. Moreover, haloperidol-induced H3 phosphorylation was unaltered in MSK1-knockout mice. These data indicate that, in striatopallidal MSNs, H3 phosphorylation is controlled by the opposing actions of D2Rs and A2ARs. Thus, blockade of D2Rs promotes histone H3 phosphorylation through the A2AR-mediated activation of Gαolf and inhibition of protein phosphatase-1 (PP-1) through the PKA-dependent phosphorylation of DARPP-32.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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Created: Tue, 29 Jul 2014, 15:16:30 EST by J Bertran Gonzalez on behalf of Clem Jones Centre for Ageing Dementia Research