Central role of alpha7 nicotinic receptor in differentiation of the stratified squamous epithelium.
Central role of alpha7 nicotinic receptor in differentiation of the stratified squamous epithelium.
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DOI：
10.1083/jcb.200206096
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发表时间：
2002-10-28
期刊：
影响因子：
--
通讯作者：
Grando SA
中科院分区：
文献类型：
--
作者：
Arredondo J;Nguyen VT;Chernyavsky AI;Bercovich D;Orr-Urtreger A;Kummer W;Lips K;Vetter DE;Grando SA
几种神经节型烟碱型乙酰胆碱受体(NAChR)在非神经元部位大量表达，但其功能尚不清楚。我们发现角质形成细胞α7nAChR控制着形成皮肤屏障所需的表皮角质形成细胞的动态平衡和终末分化。用α-银环蛇毒素或反义寡核苷酸处理角质形成细胞单层，研究α-7nAChR功能失活对角质形成细胞周期进程、分化和凋亡的影响，以及在缺乏α7nAChR通道的纯合子小鼠皮肤中的作用。α7信号通路的消除阻断了尼古丁诱导的45Ca2+内流，并在转录和/或翻译水平上抑制了这些细胞的终末分化。另一方面，抑制α7nAChR通路有利于细胞周期进程。在α7−/−小鼠的表皮中，角质形成细胞基因表达的异常与以表皮更新延迟为特征的表型变化有关。α7的缺失与α3的表达上调有关，该通道含有缺失α5亚单位的nAChR通道，以及由同源α9和异构体α9α10产生的nAChR。因此，本研究表明，通过α7nAChR通道的ACh信号通过调节细胞周期进程、细胞凋亡和终末分化基因的表达来控制表皮角质形成细胞的后期发育，并且这些作用至少部分是通过改变跨膜Ca~(2+)内流来调节的。
Several ganglionic nicotinic acetylcholine receptor (nAChR) types are abundantly expressed in nonneuronal locations, but their functions remain unknown. We found that keratinocyte α7 nAChR controls homeostasis and terminal differentiation of epidermal keratinocytes required for formation of the skin barrier. The effects of functional inactivation of α7 nAChR on keratinocyte cell cycle progression, differentiation, and apoptosis were studied in cell monolayers treated with α-bungarotoxin or antisense oligonucleotides and in the skin of Acra7 homozygous mice lacking α7 nAChR channels. Elimination of the α7 signaling pathway blocked nicotine-induced influx of 45Ca2+ and also inhibited terminal differentiation of these cells at the transcriptional and/or translational level. On the other hand, inhibition of the α7 nAChR pathway favored cell cycle progression. In the epidermis of α7−/− mice, the abnormalities in keratinocyte gene expression were associated with phenotypic changes characteristic of delayed epidermal turnover. The lack of α7 was associated with up-regulated expression of the α3 containing nAChR channels that lack α5 subunit, and both homomeric α9- and heteromeric α9α10-made nAChRs. Thus, this study demonstrates that ACh signaling through α7 nAChR channels controls late stages of keratinocyte development in the epidermis by regulating expression of the cell cycle progression, apoptosis, and terminal differentiation genes and that these effects are mediated, at least in part, by alterations in transmembrane Ca2+ influx.
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