Amphetamine-induced decreases in dopamine transporter surface expression are protein kinase C-independent
Amphetamine-induced decreases in dopamine transporter surface expression are protein kinase C-independent
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DOI：
10.1016/j.neuropharm.2007.11.007
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发表时间：
2008-03-01
影响因子：
4.7
通讯作者：
Melikian, Haley E.
中科院分区：
文献类型：
--
作者：
Boudanova, Ekaterina;Navaroli, Deanna A.;Melikian, Haley E.
安非他明（AMPH）是一种有效的多巴胺（DA）转运蛋白（DAT）抑制剂，可显著增加细胞外DA水平。除了其作为DAT拮抗剂的作用外，急性AMPH暴露诱导DAT从质膜损失，这涉及转运蛋白特异性膜贩运苯丙胺的作用。尽管有报道AMPH调节DAT表面表达，但导致这种效应的运输机制目前尚未确定。我们最近报道了DAT残基587-596在组成性和蛋白激酶C（PKC）加速的DAT内化中起着不可或缺的作用。在目前的研究中，我们测试了PKC刺激的DAT内化所需的结构决定因素是否是AMPH诱导的DAT螯合所必需的。急性安非他明暴露增加DAT内吞率，但DAT羧基末端残基587-590，这是所需的PKC刺激的内化，不需要AMPH加速DAT内吞。AMPH减少DAT内吞再循环，但不调节转铁蛋白受体再循环，表明AMPH不会在全球范围内减少内吞再循环。最后，用PKC抑制剂治疗表明，AMPH诱导的DAT从质膜的损失不依赖于PKC活性。这些结果表明，负责AMPH介导的DAT内化的机制是独立于那些管理PKC敏感的DAY内吞作用。(c)2007爱思唯尔有限公司保留所有权利。
Amphetamine (AMPH) is a potent dopamine (DA) transporter (DAT) inhibitor that markedly increases extracellular DA levels. In addition to its actions as a DAT antagonist, acute AMPH exposure induces DAT losses from the plasma membrane, implicating transporter-specific membrane trafficking in amphetamine's actions. Despite reports that AMPH modulates DAT surface expression, the trafficking mechanisms leading to this effect are currently not defined. We recently reported that DAT residues 587-596 play an integral role in constitutive and protein kinase C (PKC)-accelerated DAT internalization. In the current study, we tested whether the structural determinants required for PKC-stimulated DAT internalization are necessary for AMPH-induced DAT sequestration. Acute amphetamine exposure increased DAT endocytic rates, but DAT carboxy terminal residues 587-590, which are required for PKC-stimulated internalization, were not required for AMPH-accelerated DAT endocytosis. AMPH decreased DAT endocytic recycling, but did not modulate transferrin receptor recycling, suggesting that AMPH does not globally diminish endocytic recycling. Finally, treatment with a PKC inhibitor demonstrated that AMPH-induced DAT losses from the plasma membrane were not dependent upon PKC activity. These results suggest that the mechanisms responsible for AMPH-mediated DAT internalization are independent from those governing PKC-sensitive DAY endocytosis. (c) 2007 Elsevier Ltd. All rights reserved.