Ubiquilin-1 regulates nicotine-induced up-regulation of neuronal nicotinic acetylcholine receptors
Ubiquilin-1 regulates nicotine-induced up-regulation of neuronal nicotinic acetylcholine receptors
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DOI：
10.1074/jbc.m506781200
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发表时间：
2005-10-07
影响因子：
4.8
通讯作者：
Feng, GP
中科院分区：
文献类型：
--
作者：
Ficklin, MB;Zhao, SL;Feng, GP
长期接触尼古丁，就像吸烟一样，上调神经元中烟碱型乙酰胆碱受体的表面表达。这种上调被认为在尼古丁成瘾和戒断中发挥作用。尼古丁诱导的表面烟碱型乙酰胆碱受体上调背后的调节机制仍未确定。最近有研究表明，尼古丁刺激通过增加受体亚基的组装和成熟而发挥作用，形成功能性的五聚体受体。对肌肉烟碱型乙酰胆碱受体的研究表明，内质网中未组装的亚单位的可用性可以通过泛素-蛋白酶体途径进行调节，从而导致表面表达的改变。在这里，我们描述了泛素样蛋白-1在调节尼古丁诱导的神经元烟碱型乙酰胆碱受体上调中的作用。泛素样蛋白具有与蛋白酶体和泛素连接酶相互作用的能力。泛素-1在异种细胞中共表达时与未组装的α3和α4亚基相互作用，并与神经元内源性烟碱型乙酰胆碱受体相互作用。泛素-1和神经型烟碱型乙酰胆碱受体在异种细胞中的共表达显著降低了细胞表面受体的表达。在培养的颈上神经节细胞中，泛奎林-1的表达可取消尼古丁诱导的烟碱型乙酰胆碱受体的上调，但对表面受体的基础水平没有影响。免疫共染色显示，泛素-1与α3亚基的相互作用将受体亚基和蛋白小体结合成一个复合体。这些数据表明，泛奎林-1通过将未组装的尼古丁乙酰胆碱受体亚单位吸引到蛋白小体上，从而调节尼古丁诱导的上调，从而限制了神经元中未组装的尼古丁受体亚单位的可用性。
Chronic exposure to nicotine, as in tobacco smoking, up-regulates nicotinic acetylcholine receptor surface expression in neurons. This up-regulation has been proposed to play a role in nicotine addiction and withdrawal. The regulatory mechanisms behind nicotine-induced up-regulation of surface nicotinic acetylcholine receptors remain to be determined. It has recently been suggested that nicotine stimulation acts through increased assembly and maturation of receptor subunits into functional pentameric receptors. Studies of muscle nicotinic acetylcholine receptors suggest that the availability of unassembled subunits in the endoplasmic reticulum can be regulated by the ubiquitin-proteosome pathway, resulting in altered surface expression. Here, we describe a role for ubiquilin-1, a ubiquitin-like protein with the capacity to interact with both the proteosome and ubiquitin ligases, in regulating nicotine-induced up-regulation of neuronal nicotinic acetylcholine receptors. Ubiquilin-1 interacts with unassembled alpha 3 and alpha 4 subunits when coexpressed in heterologous cells and interacts with endogenous nicotinic acetylcholine receptors in neurons. Coexpression of ubiquilin-1 and neuronal nicotinic acetylcholine receptors in heterologous cells dramatically reduces the expression of the receptors on the cell surface. In cultured superior cervical ganglion neurons, expression of ubiquilin-1 abolishes nicotine-induced up-regulation of nicotinic acetylcholine receptors but has no effect on the basal level of surface receptors. Coimmunostaining shows that the interaction of ubiquilin-1 with the alpha 3 subunit draws the receptor subunit and proteosome into a complex. These data suggest that ubiquilin-1 limits the availability of unassembled nicotinic acetylcholine receptor subunits in neurons by drawing them to the proteosome, thus regulating nicotine-induced up-regulation.