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首页> 外文期刊>The FASEB Journal >Differential targeting of the dopamine transporter to recycling or degradative pathways during amphetamine- or PKC-regulated endocytosis in dopamine neurons
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Differential targeting of the dopamine transporter to recycling or degradative pathways during amphetamine- or PKC-regulated endocytosis in dopamine neurons

机译：多巴胺转运蛋白在多巴胺神经元中的含量或PKC调节的内吞作用期间再循环或降解途径的差异靶向

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The dopamine transporter (DAT) clears the extracellular dopamine released during neurotransmission and is a major target for both therapeutic and addictive psychostimulant amphetamines. Amphetamine exposure or activation of protein kinase C (PKC) by the phorbol ester PMA has been shown to down-regulate cell surface DAT. However, in dopamine neurons, the trafficking itinerary and fate of internalized DAT has not been elucidated. By monitoring surface-labeled DAT in transfected dopamine neurons from embryonic rat mesencephalic cultures, we find distinct sorting and fates of internalized DAT after amphetamine or PMA treatment. Although both drugs promote DAT internalization above constitutive endocytosis in dopamine neurons, PMA induces ubiquitination of DAT and leads to accumulation of DAT on LAMP1-positive endosomes. In contrast, after amphetamine exposure DAT is sorted to recycling endosomes positive for Rab11 and the transferrin receptor. Furthermore, quantitative assessment of DAT recycling using an antibody-feeding assay reveals that significantly less DAT returns to the surface of dopamine neurons after internalization by PMA, compared with vehicle or amphetamine treatment. These results demonstrate that, in neurons, the DAT is sorted differentially to recycling and degradative pathways after psychostimulant exposure or PKC activation, which may allow for either the transient or sustained inhibition of DAT during dopamine neurotransmission.—Hong, W. C., Amara, S. G. Differential targeting of the dopamine transporter to recycling or degradative pathways during amphetamine- or PKC-regulated endocytosis in dopamine neurons.
机译：多巴胺转运蛋白（DAT）清除神经递质期间释放的细胞外多巴胺，并且是治疗和上瘾的精神疗手的主要靶标。通过Phorbol酯PMA显示苯丙胺暴露或激活蛋白激酶C（PKC），已显示下调细胞表面DAT。然而，在多巴胺神经元中，贩运了内化数据的行程和命运尚未得到阐明。通过在转染的多巴胺神经元中监测表面标记的DAT，从胚胎大鼠思维培养物中发现了疗法或PMA治疗后内化DAT的不同分类和束缚。虽然两种药物促进了多巴胺神经元的组成型内吞作用以上的DAT内化，但PMA诱导DAT的泛素，并导致DAT在灯1阳性内体上的积累。相反，在含疗中的暴露之后，将DIR分类为回收rab11和转铁蛋白受体的阳性剂。此外，使用抗体饲养测定的DAT回收定量评估显示，与载体或含量的载体或安非他明治疗相比，PMA在内化后，DAT返回到多巴胺神经元的表面上的DEA。这些结果表明，在神经元中，DAT差异地分类到精神疗法暴露或PKC活化后的再循环和降解途径，这可能允许在多巴胺神经递质期间DAT的瞬态或持续抑制。-HONG，WC，AMARA，SG差异在多巴胺神经元中的疗法中的含量或PKC调节的内吞作用期间的多巴胺转运蛋白靶向或降解途径。

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