Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1

Bonito-Oliva, Alessandra, Pallottino, Simone, Bertran-Gonzalez, Jesus, Girault, Jean-Antoine, Valjent, Emmanuel and Fisone, Gilberto (2013) Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. Neuropharmacology, 72 197-203. doi:10.1016/j.neuropharm.2013.04.043


Author Bonito-Oliva, Alessandra
Pallottino, Simone
Bertran-Gonzalez, Jesus
Girault, Jean-Antoine
Valjent, Emmanuel
Fisone, Gilberto
Title Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1
Journal name Neuropharmacology   Check publisher's open access policy
ISSN 0028-3908
1873-7064
Publication date 2013-09
Sub-type Article (original research)
DOI 10.1016/j.neuropharm.2013.04.043
Open Access Status
Volume 72
Start page 197
End page 203
Total pages 7
Place of publication Oxford United Kingdom
Publisher Pergamon
Language eng
Formatted abstract
The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. We found that administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which preferentially express dopamine D2 receptors (D2Rs). This effect was abolished by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1.
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, 14:37:13 EST by J Bertran Gonzalez on behalf of Clem Jones Centre for Ageing Dementia Research