Nicotine regulates DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) phosphorylation at multiple sites in neostriatal neurons.
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.
Hamada
Miho
M
Department of Pharmacology, Kurume University School of Medicine, Fukuoka, Japan.
Hendrick
Joseph P
JP
Ryan
Gregory R
GR
Kuroiwa
Mahomi
M
Higashi
Hideho
H
Tanaka
Masatoshi
M
Nairn
Angus C
AC
Greengard
Paul
P
Nishi
Akinori
A
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
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018722:Nicotinic Agonists; D017447:Receptors, Dopamine D1; D009538:Nicotine