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NEUROPHARMACOLOGY

Nicotine Regulates DARPP-32 (Dopamine- and cAMP-Regulated Phosphoprotein of 32 kDa) Phosphorylation at Multiple Sites in Neostriatal Neurons

Department of Physiology (M.H., H.H., A.N.) and Pharmacology (M.K., M.T., A.N.), Kurume University School of Medicine, Kurume, Fukuoka, Japan; IntraCellular Therapies, Inc., New York, New York (J.P.H., G.R.R); Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.C.N.); and Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York (A.C.N., P.G., A.N.)

Nicotinic acetylcholine receptors (nAChRs) regulate dopaminergic signaling in the striatum by modulating the release of neurotransmitters. We have recently reported that nicotine stimulates the release of dopamine via 42^* nAChRs and/or 7 nAChRs, leading to the regulation of DARPP-32 at Thr34, the site involved in regulation of protein phosphatase-1 (PP-1). In this study, we investigated the regulation of DARPP-32 phosphorylation at its other sites, Thr75 [cyclin-dependent kinase-5 (Cdk5) site], Ser97 (CK2 site), and Ser130 (CK1 site), that serve to modulate Thr34 phosphorylation and dephosphorylation. In neostriatal slices, nicotine (100 µM) increased phosphorylation of DARPP-32 at Ser97 and Ser130 at an early time point (30 s) and decreased phosphorylation of DARPP-32 at Thr75 at a late time point (3 min). The increase in Ser97 and Ser130 phosphorylation was mediated through the release of dopamine via activation of 42^* nAChRs and 7 nAChRs and the subsequent activation of dopamine D1 and D2 receptors. The decrease in Thr75 phosphorylation was mediated through the release of dopamine via activation of 42^* nAChRs and the subsequent activation of dopamine D1 receptors. These various actions of nicotine on modulatory sites of phosphorylation would be predicted to result in a synergistic increase in the state of phosphorylation of DARPP-32 at Thr34 and thus would contribute to increased dopamine D1 receptor/DARPP-32 Thr34/PP-1 signaling.

Address correspondence to: Dr. Akinori Nishi, Department of Pharmacology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. E-mail: nishia{at}med.kurume-u.ac.jp

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