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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Truncation of human dopamine transporter by protease calpain.
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Truncation of human dopamine transporter by protease calpain.

机译：蛋白酶钙蛋白酶截短人多巴胺转运蛋白。

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摘要

It has been shown recently that the N-terminal domain of the dopamine transporter (DAT) plays a role in several transporter functions. Here we provide evidence for a possible cellular mechanism of how the N-terminus of dopamine transporter might be removed in vivo. We isolated a recombinant N-terminal protein region of human dopamine transporter and cleaved it with calpain protease. Peptide fragment analysis revealed the existence of two calpain cleavage sites at positions Thr43/Ser44 and Leu71/Ser72 of the DATN-terminus. We show that calpain activation in rat striatal synaptosomes leads to a rapid decrease of dopamine transporter N-terminal epitopes corresponding to the protein sequences removed by a calpain cleavage at Thr43/Ser44 and that the process is totally blocked by a calpain inhibitor. Calpain truncation of the DATN-terminus abolishes its interaction with the receptor of activated protein kinase C, RACK1 and removes protein sequences previously implicated in amphetamine-induced dopamine release, PKC-dependent endocytosis and the interaction of DAT with the dopamine D2 receptor. The above suggests that cleavage of DAT by calpain may significantly modify dopamine homeostasis under pathological or physiological conditions.
机译：最近显示，多巴胺转运蛋白（DAT）的N-末端结构域在几种转运蛋白功能中起作用。在这里，我们为多巴胺转运蛋白的N端如何在体内被移除的可能的细胞机制提供了证据。我们分离了人多巴胺转运蛋白的重组N末端蛋白区域，并用钙蛋白酶蛋白酶对其进行了切割。肽片段分析显示在DATN末端的Thr43 / Ser44和Leu71 / Ser72位置存在两个钙蛋白酶切割位点。我们显示，大鼠纹状体突触体中的钙蛋白酶激活会导致多巴胺转运蛋白N末端表位的快速降低，这对应于在Thr43 / Ser44处的钙蛋白酶裂解所去除的蛋白质序列，并且该过程被钙蛋白酶抑制剂完全阻断了。 DATN末端的钙蛋白酶截短取消了它与活化蛋白激酶C RACK1受体的相互作用，并消除了以前与苯丙胺诱导的多巴胺释放，PKC依赖的内吞作用以及DAT与多巴胺D2受体的相互作用有关的蛋白序列。以上表明钙蛋白酶对DAT的切割可在病理或生理条件下显着改变多巴胺稳态。

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