Chen Rong, Furman Cheryse A, Gnegy Margaret E
Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, MI 48109-5632, USA Tel.: +1 734 763 3083
Future Neurol. 2010 Jan 1;5(1):123. doi: 10.2217/fnl.09.76.
The dopamine transporter (DAT) is a primary determinant of the concentration of dopamine in the synapse and is involved in a number of psychiatric and neurological diseases. The transporter actively takes up its physiological substrate, dopamine, when it is on the surface of the plasmalemmal membrane, but the concentration of DAT in the membrane is highly regulated by substrate. Substrates initially, and very rapidly, recruit more DAT into the membrane for greater function, but continued presence of substrate downregulates the activity of DAT and even membrane DAT content. This biphasic regulation is orchestrated by numerous signal transduction mechanisms, including a palette of protein kinases. Understanding the mechanisms of rapid regulation of DAT could provide new therapeutic strategies to improve transporter function and modulate responses to its more notorious substrates, amphetamine and methamphetamine.
多巴胺转运体（DAT）是突触中多巴胺浓度的主要决定因素，并与多种精神和神经疾病有关。当转运体位于质膜表面时，它会主动摄取其生理底物多巴胺，但膜中DAT的浓度受到底物的高度调节。底物最初会非常迅速地将更多DAT招募到膜中以增强功能，但底物的持续存在会下调DAT的活性，甚至降低膜中DAT的含量。这种双相调节是由多种信号转导机制精心安排的，包括一系列蛋白激酶。了解DAT快速调节的机制可以提供新的治疗策略，以改善转运体功能并调节对其更臭名昭著的底物苯丙胺和甲基苯丙胺的反应。
