Identification of Piccolo as a regulator of behavioral plasticity and dopamine transporter internalization
Identification of Piccolo as a regulator of behavioral plasticity and dopamine transporter internalization
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DOI：
10.1038/sj.mp.4002132
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发表时间：
2008-04-01
影响因子：
11
通讯作者：
Nabeshima, T.
中科院分区：
文献类型：
--
作者：
Cen, X.;Nitta, A.;Nabeshima, T.
多巴胺转运蛋白（DAT）内化是甲基苯丙胺（METH）等成瘾药物导致多巴胺再摄取减少的一种机制。我们发现一种突触前支架蛋白Piccolo在反复给药的小鼠伏隔核（NAc）中过表达。反义技术对短笛的低表达增强了冰毒诱导的NAc行为致敏、条件奖励和突触多巴胺积累。在表达人DAT的PC12细胞中，Piccolo C(2)A结构域的表达减弱了甲基甲氧胺诱导的多巴胺摄取抑制。与此一致的是，它减缓了甲基苯丙胺引起的加速的DAT内化，从而维持了质层DAT的呈现。在免疫染色和结构建模中，Piccolo C(2)A结构域显示出隔离膜磷脂酰肌醇4,5-二磷酸的不寻常特征，这可能是其在调节DAT内化中的作用的基础。总之，我们的研究结果表明，甲基安非他明诱导的短笛上调代表了NAc对过度多巴胺能传递的稳态反应。Piccolo C(2)A结构域可能作为细胞骨架的调节因子，调控细胞质DAT内化，这可能是其行为可塑性的基础。
Dopamine transporter (DAT) internalization is a mechanism underlying the decreased dopamine reuptake caused by addictive drugs like methamphetamine (METH). We found that Piccolo, a presynaptic scaffolding protein, was overexpressed in the nucleus accumbens (NAc) of the mice repeatedly administrated with METH. Piccolo downexpression by antisense technique augmented METH-induced behavioral sensitization, conditioned reward and synaptic dopamine accumulation in NAc. Expression of Piccolo C(2)A domain attenuated METH-induced inhibition of dopamine uptake in PC12 cells expressing human DAT. Consistent with this, it slowed down the accelerated DAT internalization induced by METH, thus maintaining the presentation of plasmalemmal DAT. In immunostaining and structural modeling Piccolo C(2)A domain displays an unusual feature of sequestering membrane phosphatidylinositol 4,5-bisphosphate, which may underlie its role in modulating DAT internalization. Together, our results indicate that Piccolo upregulation induced by METH represents a homeostatic response in the NAc to excessive dopaminergic transmission. Piccolo C(2)A domain may act as a cytoskeletal regulator for plasmalemmal DAT internalization, which may underlie its contributions in behavioral plasticity.