Map of dopamine signaling in the neostriatum

多巴胺在大脑的精神运动功能调节中起着核心作用。多巴胺的许多作用是通过涉及DARPP-32(多巴胺和cAMP调节的32 kDa磷酸蛋白)的信号转导途径来实现的。当DARPP-32在Thr34上被磷酸化时，它被转化为蛋白磷酸酶-1(PP-1)的有效抑制物，从而控制下游许多生理效应物的磷酸化状态和活性。我们最近报道尼古丁通过α4β2^*nAChRs和/或α7nAChRs刺激多巴胺的释放，从而导致Thr34处DARPP-32的调节，而Thr34参与了蛋白磷酸酶-1(PP-1)的调节。在这项研究中，我们研究了DARPP-32在其其他位点Thr75(CDK5位点)、Ser97(CK2位点)和Ser130(CK1位点)上对T34磷酸化和去磷酸化的调节。在新纹状体脑片中，尼古丁(100μM)在早期(30min)增加第97位和第130位的DARPP-32的磷酸化，在晚期(3min)降低第75位的DARPP-32的磷酸化。Ser97和Ser130磷酸化的增加是通过激活α4β2^*nAChRs和A7nAChRs以及随后激活多巴胺D1和D2受体而释放多巴胺来实现的。Thr75磷酸化的降低是通过激活α4β2^*nAChRs和随后激活多巴胺D1受体而释放多巴胺来实现的。尼古丁对磷酸化调节位点的这些不同作用将被预测为导致Thr34处DARPP-32磷酸化状态的协同增加，从而有助于增加多巴胺D1受体/DARPP-32Thr34/PP-1信号。

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.