| First Author | Bonito-Oliva A | Year | 2013 |
| Journal | Neuropharmacology | Volume | 72 |
| Pages | 197-203 | PubMed ID | 23643747 |
| Mgi Jnum | J:255110 | Mgi Id | MGI:6099321 |
| Doi | 10.1016/j.neuropharm.2013.04.043 | Citation | Bonito-Oliva A, et al. (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 |
| abstractText | 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. |
