Map of dopamine signaling in the neostriatum

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Dopamine plays a central role in the regulation of psychomotor function in the brain. Many of the actions of dopamine are mediated through signal transduction pathways that involve DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of M_r 32 kDa). When DARPP-32 is phosphorylated on Thr34, it is converted into a potent inhibitor of protein phosphatase-1 (PP-1), and thereby controls the phosphorylation state and activity of many downstream physiological effectors. It is extremely important to identify signaling cascades activated by dopamine and other neurotransmitters to understand the functions of neotriatum under physiological and pathophysiological conditions.We have recently reported that nicotine stimulates the release of dopamine via α4β2^* nAChRs and/or α7 nAChRs, leading to 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 (Cdk5 site), Ser97 (CK2 site), and Ser130 (CK1.site), that serve to modulate T34 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 α4β2^* nAChRs and a7 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 α4β2^* 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.