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首页> 外文期刊>Cellular Physiology and Biochemistry >Investigation of the Inhibitory Effects of the Benzodiazepine Derivative, 5-BDBD on P2X4 Purinergic Receptors by two Complementary Methods
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Investigation of the Inhibitory Effects of the Benzodiazepine Derivative, 5-BDBD on P2X4 Purinergic Receptors by two Complementary Methods

机译：两种补充方法研究苯二氮卓衍生物5-BDBD对P2X4嘌呤能受体的抑制作用

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Background/Aims: ATP-gated P2X4 purinergic receptors (P2X4Rs) are cation channels with important roles in diverse cell types. To date, lack of specific inhibitors has hampered investigations on P2X4Rs. Recently, the benzodiazepine derivative, 5-BDBD has been proposed to selectively inhibit P2X4Rs. However, limited evidences are currently available on its inhibitory properties. Thus, we aimed to characterize the inhibitory effects of 5-BDBD on recombinant human P2X4Rs. Methods: We investigated ATP-induced intracellular Ca2+ signals and whole cell ion currents in HEK 293 cells that were either transiently or stably transfected with hP2X4Rs. Results: Our data show that ATP (< 1 μM) stimulates P2X4R-mediated Ca2+ influx while endogenously expressed P2Y receptors are not activated to any significant extent. Both 5-BDBD and TNP-ATP inhibit ATP-induced Ca2+ signals and inward ion currents in a concentration-dependent manner. Application of two different concentrations of 5-BDBD causes a rightward shift in ATP dose-response curve. Since the magnitude of maximal stimulation does not change, these data suggest that 5-BDBD may competitively inhibit the P2X4Rs. Conclusions: Our results demonstrate that application of submicromolar ATP concentrations allows reliable assessment of recombinant P2XR functions in HEK 293 cells. Furthermore, 5-BDBD and TNP-ATP have similar inhibitory potencies on the P2X4Rs although their mechanisms of actions are different.
机译：背景/目的：ATP门控的P2X 4 嘌呤能受体（P2X 4 Rs）是在多种细胞类型中起重要作用的阳离子通道。迄今为止，缺乏特异性抑制剂阻碍了对P2X 4 Rs的研究。最近，有人提出苯二氮卓衍生物5-BDBD选择性抑制P2X 4 Rs。然而，目前关于其抑制性质的证据有限。因此，我们旨在表征5-BDBD对重组人P2X 4 Rs的抑制作用。方法：我们研究了被hP2X 4 Rs瞬时或稳定转染的HEK 293细胞中ATP诱导的细胞内Ca 2 + 信号和全细胞离子电流。结果：我们的数据显示，ATP（<1μM）刺激P2X 4 R介导的Ca 2 + 内流，而内源性表达的P2Y受体没有被激活。 5-BDBD和TNP-ATP均以浓度依赖的方式抑制ATP诱导的Ca 2 + 信号和内向离子流。两种不同浓度的5-BDBD的使用会导致ATP剂量反应曲线向右移动。由于最大刺激的幅度没有变化，这些数据表明5-BDBD可能竞争性抑制P2X 4 Rs。结论：我们的结果表明亚微摩尔ATP浓度的应用可以可靠地评估HEK 293细胞中重组P2XR的功能。此外，5-BDBD和TNP-ATP对P2X 4 Rs的抑制作用相似，尽管它们的作用机理不同。

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