title: Nicotine regulates DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) phosphorylation at multiple sites in neostriatal neurons.
abstract: 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 alpha4beta2(*) nAChRs and/or alpha7 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 microM) 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 alpha4beta2(*) nAChRs and alpha7 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 alpha4beta2(*) 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.
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Fukuoka, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Hamada
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hendrick
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Ryan
authors.forename: Mahomi
authors.initials: M
authors.lastname: Kuroiwa
authors.forename: Hideho
authors.initials: H
authors.lastname: Higashi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tanaka
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000918:Antibody Specificity; D015153:Blotting, Western; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D004357:Drug Synergism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010766:Phosphorylation; D017447:Receptors, Dopamine D1 / Q000187:drug effects
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018722:Nicotinic Agonists; D017447:Receptors, Dopamine D1; D009538:Nicotine