title: Haloperidol regulates the state of phosphorylation of ribosomal protein S6 via activation of PKA and phosphorylation of DARPP-32.
abstract: Administration of typical antipsychotic drugs, such as haloperidol, promotes cAMP-dependent signaling in the medium spiny neurons (MSNs) of the striatum. In this study, we have examined the effect of haloperidol on the state of phosphorylation of the ribosomal protein S6 (rpS6), a component of the small 40S ribosomal subunit. We found that haloperidol increases the phosphorylation of rpS6 at the dual site Ser235/236, which is involved in the regulation of mRNA translation. This effect was exerted in the MSNs of the indirect pathway, which express specifically dopamine D2 receptors (D2Rs) and adenosine A2 receptors (A2ARs). The effect of haloperidol was decreased by blockade of A2ARs or by genetic attenuation of the Gα(olf) protein, which couples A2ARs to activation of adenylyl cyclase. Moreover, stimulation of cAMP-dependent protein kinase A (PKA) increased Ser235/236 phosphorylation in cultured striatal neurons. The ability of haloperidol to promote rpS6 phosphorylation was abolished in knock-in mice deficient for PKA activation of the protein phosphatase-1 inhibitor, dopamine- and cAMP-regulated phosphoprotein of 32 kDa. In contrast, pharmacological or genetic inactivation of p70 rpS6 kinase 1, or extracellular signal-regulated kinases did not affect haloperidol-induced rpS6 phosphorylation. These results identify PKA as a major rpS6 kinase in neuronal cells and suggest that regulation of protein synthesis through rpS6 may be a potential target of antipsychotic drugs.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Valjent
authors.forename: Jesus
authors.initials: J
authors.lastname: Bertran-Gonzalez
authors.forename: Heather
authors.initials: H
authors.lastname: Bowling
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lopez
authors.forename: Emanuela
authors.initials: E
authors.lastname: Santini
authors.forename: Miriam
authors.initials: M
authors.lastname: Matamales
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bonito-Oliva
authors.forename: Denis
authors.initials: D
authors.lastname: Hervé
authors.forename: Charles
authors.initials: C
authors.lastname: Hoeffer
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Girault
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fisone
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D055879:Gene Knock-In Techniques; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D038601:Ribosomal Protein S6 / Q000378:metabolism*
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497929:Ppp1r1b protein, mouse; D038601:Ribosomal Protein S6; D017868:Cyclic AMP-Dependent Protein Kinases; D006220:Haloperidol