Foster J D, Cervinski M A, Gorentla B K, Vaughan R A
Department of Biochemistry and Molecular Biology, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND 58203, USA.
Handb Exp Pharmacol. 2006(175):197-214. doi: 10.1007/3-540-29784-7_10.
The dopamine transporter (DAT) is a neuronal phosphoprotein and target for psychoactive drugs that plays a critical role in terminating dopaminergic transmission by reuptake of dopamine from the synaptic space. Control of DAT activity and plasma membrane expression are therefore central to drug actions and the spatial and temporal regulation of synaptic dopamine levels. DATs rapidly traffic between the plasma membrane and endosomal compartments in both constitutive and protein kinase C-dependent manners. Kinase activators, phosphatase inhibitors, and transported substrates modulate DAT phosphorylation and activity, but the underlying mechanisms and role of phosphorylation in these processes are poorly understood. Complex adaptive changes in DAT function potentially related to these processes are also induced by psychostimulant and therapeutic transport blockers such as cocaine and methylphenidate. This chapter provides an overview of the current state of knowledge regarding DAT phosphorylation and its relationship to transporter activity and trafficking. A better understanding of how dopaminergic neurons regulate DAT function and the role of phosphorylation may lead to the identification of novel therapeutic targets for the treatment and prevention of dopaminergic disorders.
多巴胺转运体（DAT）是一种神经元磷蛋白，也是精神活性药物的作用靶点，它通过从突触间隙重新摄取多巴胺在终止多巴胺能传递中起关键作用。因此，控制DAT活性和质膜表达对于药物作用以及突触多巴胺水平的时空调节至关重要。DAT以组成型和蛋白激酶C依赖性方式在质膜和内体区室之间快速转运。激酶激活剂、磷酸酶抑制剂和转运底物可调节DAT的磷酸化和活性，但这些过程中磷酸化的潜在机制和作用尚不清楚。精神兴奋剂和治疗性转运阻滞剂（如可卡因和哌甲酯）也会诱导与这些过程潜在相关的DAT功能的复杂适应性变化。本章概述了关于DAT磷酸化及其与转运体活性和转运关系的当前知识状态。更好地理解多巴胺能神经元如何调节DAT功能以及磷酸化的作用，可能会导致识别出用于治疗和预防多巴胺能疾病的新治疗靶点。
