Natural compounds with P2X7 receptor-modulating properties
Natural compounds with P2X7 receptor-modulating properties
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DOI：
10.1007/s11302-013-9392-1
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发表时间：
2014-06-01
影响因子：
3.5
通讯作者：
Schaefer, Michael
中科院分区：
文献类型：
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作者：
Fischer, Wolfgang;Urban, Nicole;Schaefer, Michael
腺苷5 '-三磷酸（ATP）门控P2 X7受体是一种膜结合的非选择性阳离子通道，在多种细胞类型中表达。P2 X7感知高细胞外ATP浓度，并且似乎涉及广泛的细胞功能以及病理生理过程，包括免疫应答和炎症、胶质递质和细胞因子的释放、癌细胞生长或神经退行性疾病的发展。在本研究中，我们使用稳定表达人P2 X7的HEK 293细胞系和荧光成像酶标仪技术鉴定了可以阻断或敏化ATP（1 mM）诱导的Ca 2+反应的天然化合物和类似物。例如，替尼泊苷在亚微摩尔浓度下有效地阻断人P2 X7，但不阻断人P2 X4或大鼠P2 X2。在表达P2 X7的人A375黑色素瘤细胞和小鼠小胶质细胞中也观察到ATP诱导的Ca 2+进入和Yo-Pro-1摄取的显著阻断。另一方面，龙舌兰碱（AGL）和藤黄酸（GA）促进了所有三个细胞群中的P2 X7对ATP的反应。GA还增强了YO-PRO-1的摄取，而AGL不影响ATP刺激的细胞内积累的这种染料。根据P2 X7在各种疾病中的病理生理学作用，选择性调节剂可能具有进一步开发的潜力，例如作为神经保护或神经保护药物。
The adenosine 5'-triphosphate (ATP)-gated P2X7 receptor is a membrane-bound, non-selective cation channel, expressed in a variety of cell types. The P2X7 senses high extracellular ATP concentrations and seems to be implicated in a wide range of cellular functions as well as pathophysiological processes, including immune responses and inflammation, release of gliotransmitters and cytokines, cancer cell growth or development of neurodegenerative diseases. In the present study, we identified natural compounds and analogues that can block or sensitize the ATP (1 mM)-induced Ca2+ response using a HEK293 cell line stably expressing human P2X7 and fluorometric imaging plate reader technology. For instance, teniposide potently blocked the human P2X7 at sub-miromolar concentrations, but not human P2X4 or rat P2X2. A marked block of ATP-induced Ca2+ entry and Yo-Pro-1 uptake was also observed in human A375 melanoma cells and mouse microglial cells, both expressing P2X7. On the other hand, agelasine (AGL) and garcinolic acid (GA) facilitated the P2X7 response to ATP in all three cell populations. GA also enhanced the YO-PRO-1 uptake, whereas AGL did not affect the ATP-stimulated intracellular accumulation of this dye. According to the pathophysiological role of P2X7 in various diseases, selective modulators may have potential for further development, e.g. as neuroprotective or antineoplastic drugs.