Piezo1 regulates mechanotransductive release of ATP from human RBCs
Piezo1 regulates mechanotransductive release of ATP from human RBCs
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DOI：
10.1073/pnas.1507309112
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发表时间：
2015-09-22
影响因子：
11.1
通讯作者：
Wan, Jiandi
中科院分区：
文献类型：
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作者：
Cinar, Eyup;Zhou, Sitong;Wan, Jiandi
Piezo蛋白(Piezo1和Piezo2)是最近在真核细胞中发现的机械激活的阳离子通道，与对触摸、压力和拉伸的生理反应有关。特别是，人类红细胞在其膜上表达Piezo1，Piezo1的突变与遗传性干细胞症有关。然而，到目前为止，Piezo1对正常红细胞的生理功能仍然知之甚少。在这里，我们展示了Piezo1通过控制剪切性诱导的钙(Ca~(2+))内流来调节人红细胞机械转导释放ATP。我们发现，在用Piezo1抑制剂处理或具有突变的Piezo1通道的人红细胞中，剪切诱导的ATP释放量和钙内流显著减少。值得注意的是，需要一个关键的细胞外钙离子浓度来触发显著的ATP释放，但红细胞中与膜相关的ATP池也有助于ATP的释放。我们的结果显示了Piezo1通道如何在正常红细胞中发挥作用，并提示了一种先前未知的ATP释放的机械转导途径。因此，我们预计这项研究将对红细胞研究、细胞机械传感以及与红细胞疾病和血管疾病相关的临床研究产生广泛影响。
Piezo proteins (Piezo1 and Piezo2) are recently identified mechanically activated cation channels in eukaryotic cells and associated with physiological responses to touch, pressure, and stretch. In particular, human RBCs express Piezo1 on their membranes, and mutations of Piezo1 have been linked to hereditary xerocytosis. To date, however, physiological functions of Piezo1 on normal RBCs remain poorly understood. Here, we show that Piezo1 regulates mechanotransductive release of ATP from human RBCs by controlling the shear-induced calcium (Ca2+) influx. We find that, in human RBCs treated with Piezo1 inhibitors or having mutant Piezo1 channels, the amounts of shear-induced ATP release and Ca2+ influx decrease significantly. Remarkably, a critical extracellular Ca2+ concentration is required to trigger significant ATP release, but membrane-associated ATP pools in RBCs also contribute to the release of ATP. Our results show how Piezo1 channels are likely to function in normal RBCs and suggest a previously unidentified mechanotransductive pathway in ATP release. Thus, we anticipate that the study will impact broadly on the research of red cells, cellular mechanosensing, and clinical studies related to red cell disorders and vascular disease.