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 Gαolf 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.
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Acknowledgements
This work was supported by Swedish Research Council Grants 20715 and 13482, the Wenner-Gren Foundations and the Agence Nationale de la Recherche (ANR) in the frame of Era-Net NEURON (project ANR-08-NEUR-006-01) (to GF), the Fondation pour la Recherche Médicale (FRM) and Grant ANR-08-BLAN-0287 (to JAG), and the National Institutes of Health Grants NS034007 and NS047384 (to EK). SL was a recipient of a postdoctoral fellowship from the FEBS. ABO was supported by the foundation Blanceflor Boncompagni-Ludovisi, née Bildt. We thank Dr Paul Greengard for providing the T34A DARPP-32 mutant mice.
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Valjent, E., Bertran-Gonzalez, J., Bowling, H. et al. Haloperidol Regulates the State of Phosphorylation of Ribosomal Protein S6 via Activation of PKA and Phosphorylation of DARPP-32. Neuropsychopharmacol 36, 2561–2570 (2011). https://doi.org/10.1038/npp.2011.144
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DOI: https://doi.org/10.1038/npp.2011.144
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