Nonclassical, distinct endocytic signals dictate constitutive and PKC-regulated neurotransmitter transporter internalization
Nonclassical, distinct endocytic signals dictate constitutive and PKC-regulated neurotransmitter transporter internalization
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DOI：
10.1038/nn1478
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发表时间：
2005-07-01
影响因子：
25
通讯作者：
Melikian, HE
中科院分区：
文献类型：
--
作者：
Holton, KL;Loder, MK;Melikian, HE
神经递质转运蛋白对突触神经递质失活至关重要。转运蛋白抑制剂显著增加突触传递的持续时间和幅度，强调了转运蛋白活性在神经传递中的重要性。最近的研究表明，膜贩运动态地管理神经元转运蛋白细胞表面的介绍蛋白激酶C调节的方式，这表明转运蛋白贩运深刻影响突触信号。然而，耦合神经递质转运蛋白的内吞机制的分子结构尚未确定。在这里，我们确定非经典的，不同的内吞信号的多巴胺转运蛋白（DAT）是必要的，足以驱动组成和蛋白激酶C调节DAT内化。DAT内化信号在SLC6神经递质载体中是保守的，并且在同源去甲肾上腺素转运蛋白中起作用，这表明该区域可能是所有SLC6神经递质转运蛋白的内吞信号。DAT内吞信号不符合经典的内化基序，这表明SLC6神经递质转运蛋白可能已经进化出独特的内吞机制。
Neurotransmitter transporters are critical for synaptic neurotransmitter inactivation. Transporter inhibitors markedly increase the duration and magnitude of synaptic transmission, underscoring the importance of transporter activity in neurotransmission. Recent studies indicate that membrane trafficking dynamically governs neuronal transporter cell-surface presentation in a protein kinase C-regulated manner, suggesting that transporter trafficking profoundly affects synaptic signaling. However, the molecular architecture coupling neurotransmitter transporters to the endocytic machinery is not defined. Here, we identify nonclassical, distinct endocytic signals in the dopamine transporter (DAT) that are necessary and sufficient to drive constitutive and protein kinase C-regulated DAT internalization. The DAT internalization signal is conserved across SLC6 neurotransmitter carriers and is functional in the homologous norepinephrine transporter, suggesting that this region is likely to be the endocytic signal for all SLC6 neurotransmitter transporters. The DAT endocytic signal does not conform to classic internalization motifs, suggesting that SLC6 neurotransmitter transporters may have evolved unique endocytic mechanisms.