Regulation of the norepinephrine transporter by α-synuclein-mediated interactions with microtubules
Regulation of the norepinephrine transporter by α-synuclein-mediated interactions with microtubules
复制标题
DOI：
10.1111/j.1460-9568.2007.05757.x
复制
发表时间：
2007-09-01
影响因子：
3.4
通讯作者：
Sidhu, Anita
中科院分区：
文献类型：
--
作者：
Jeannotte, Alexis M.;Sidhu, Anita
α-突触核蛋白（α-Syn）调节儿茶酚胺能神经传递。我们证明，α-Syn调节去甲肾上腺素转运蛋白（NET）的活性和表面表达，这取决于其表达水平。与单独用NET转染的细胞相比，在用NET和少量α-Syn共转染的细胞中，NET活性和细胞表面表达增加，蛋白质与α-Syn的相互作用减少。在较高水平的α-Syn表达下观察到匡威效应。用诺考达唑和其他微管（MT）去稳定剂处理废除了α-Syn对NET的表达依赖性双峰调节。在低α-Syn水平下，诺考达唑对NET表面表达或蛋白质相互作用没有影响，而在较高水平下诱导这些测量值增加。用NET单独转染的细胞显示对诺考达唑不敏感，表明α-Syn表达对于NET活性的MT依赖性变化是必需的。MT去稳定剂也引起脑干初级神经元和额叶皮层突触体中[H-3]-NE摄取的显著增加，但纹状体突触体不增加。这些研究结果表明，NET的表面定位和活性是由α-Syn调制的方式，既依赖于与MT细胞骨架的相互作用，并在不同的大脑区域。
alpha-Synuclein (alpha-Syn) regulates catecholaminergic neurotransmission. We demonstrate that alpha-Syn regulates the activity and surface expression of the norepinephrine transporter (NET), depending on its expression levels. In cells co-transfected with NET and low amounts of alpha-Syn, NET activity and cell surface expression were increased and protein interactions with alpha-Syn decreased, compared with cells transfected with NET alone. Converse effects were observed at higher levels of alpha-Syn expression. Treatment with nocodazole and other microtubule (MT) destabilizers abolished the expression-dependent bimodal regulation of NET by alpha-Syn. At low alpha-Syn levels, nocodazole had no effect on NET surface expression or protein interactions, while inducing increases in these measures at higher levels. Cells that were transfected with NET alone displayed no sensitivity to nocodazole, indicating that alpha-Syn expression was necessary for the MT-dependent changes in NET activity. MT destabilizers also caused a significant increase in [H-3]-NE uptake in brainstem primary neurons and synaptosomes from the frontal cortex, but not striatal synaptosomes. These findings suggest that the surface localization and activity of NET is modulated by alpha-Syn in a manner that is both dependent on interactions with the MT cytoskeleton and varies across brain regions.