Nicotine upregulates its own receptors through enhanced intracellular maturation
Nicotine upregulates its own receptors through enhanced intracellular maturation
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DOI：
10.1016/j.neuron.2005.03.029
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发表时间：
2005-05-19
期刊：
影响因子：
16.2
通讯作者：
Corringer, PJ
中科院分区：
文献类型：
--
作者：
Sallette, J;Pons, S;Corringer, PJ
长期暴露于尼古丁会引起吸烟者大脑中高亲和力尼古丁受体的上调。为了研究上调的分子机制，我们用人α 4 β 2受体转染HEK293细胞，并利用代谢标记和免疫沉淀技术追踪细胞内生物合成过程中的亚基。我们发现高甘露糖基化亚基在内质网成熟并组装成五聚体，并且只有五聚体受体在碳水化合物处理后到达细胞表面。尼古丁被证明在细胞内起作用，并增加由构象依赖的mAb290免疫沉淀的β亚基的数量，表明尼古丁促进了这些受体在细胞内成熟的关键步骤。吸烟者血液中的尼古丁浓度对SH-SY5Y神经母细胞瘤细胞中α 4 β 2的表达也会产生这种影响，这种影响可能在尼古丁成瘾中起关键作用，并可能实现神经可塑性模型。
Chronic exposure to nicotine elicits upregulation of high-affinity nicotinic receptors in the smoker's brain. To address the molecular mechanism of upregulation, we transfected HEK293 cells with human alpha 4 beta 2 receptors and traced the subunits throughout their intracellular biosynthesis, using metabolic labeling and immunoprecipitation techniques. We show that high-mannose glycosylated subunits mature and assemble into pentamers in the endoplasmic reticulum and that only pentameric receptors reach the cell surface following carbohydrate processing. Nicotine is shown to act inside the cell and to increase the amount of beta subunits immunoprecipitated by the conformation-dependent mAb290, indicating that nicotine enhances a critical step in the intracellular maturation of these receptors. This effect, which also takes place at concentrations of nicotine found in the blood of smokers upon expression of alpha 4 beta 2 in SH-SY5Y neuroblastoma cells, may play a crucial role in nicotine addiction and possibly implement a model of neural plasticity.