Map of dopamine signaling in the neostriatum

多巴胺在调节大脑的精神功能中起着核心作用。多巴胺的许多作用是通过涉及DARPP-32（多巴胺和cAMP调节的M_r 32 kDa磷蛋白）的信号转导途径介导的。当DARPP-32在Thr 34上磷酸化时，它被转化为蛋白磷酸酶-1（PP-1）的有效抑制剂，从而控制许多下游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α7 nAChRs刺激多巴胺的释放，导致DARPP-32在Thr 34的调节，该位点参与蛋白磷酸酶-1（PP-1）的调节。在这项研究中，我们研究了DARPP-32磷酸化在其其他位点的调节，Thr 75（Cdk 5位点），Ser 97（CK 2位点）和Ser 130（CK1.site），这些位点用于调节T34磷酸化和去磷酸化。在新纹状体切片中，尼古丁（100 μM）在早期时间点（30 s）增加DARPP-32在Ser 97和Ser 130的磷酸化，在晚期时间点（3 min）减少DARPP-32在Thr 75的磷酸化。Ser 97和Ser 130磷酸化的增加是通过激活α4β2^* nAChR和α 7 nAChR释放多巴胺以及随后激活多巴胺D1和D2受体介导的。Thr 75磷酸化的减少是通过α4β2^* nAChR的激活和随后多巴胺D1受体的激活而释放多巴胺介导的。预计尼古丁对磷酸化调节位点的这些不同作用将导致DARPP-32在Thr 34处磷酸化状态的协同增加，因此将有助于增加多巴胺D1受体/DARPP-32 Thr 34/PP-1信号传导。

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.