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.
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.
authors: Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden. alessandra.bonito.oliva@ki.se
authors: Alessandra
authors: A
authors: Bonito-Oliva
authors: Simone
authors: S
authors: Pallottino
authors: Jesus
authors: J
authors: Bertran-Gonzalez
authors: Jean-Antoine
authors: JA
authors: Girault
authors: Emmanuel
authors: E
authors: Valjent
authors: Gilberto
authors: G
authors: Fisone
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006220:Haloperidol / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011480:Protease Inhibitors / Q000494:pharmacology; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018756:GABA Antagonists; D046912:Multiprotein Complexes; C497929:Ppp1r1b protein, mouse; D011480:Protease Inhibitors; D011687:Purines; D038601:Ribosomal Protein S6; C424127:SL 327; C111599:istradefylline; D000607:Aminoacetonitrile; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D054645:Protein Phosphatase 1; D003024:Clozapine; D006220:Haloperidol