Piezo1 links mechanical forces to red blood cell volume.
Piezo1 links mechanical forces to red blood cell volume.
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DOI：
10.7554/elife.07370
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发表时间：
2015-05-22
期刊：
影响因子：
7.7
通讯作者：
Patapoutian A
中科院分区：
文献类型：
--
作者：
Cahalan SM;Lukacs V;Ranade SS;Chien S;Bandell M;Patapoutian A
红细胞（RBC）在再循环时会受到显著的机械力，但这些力的后果尚未完全了解。最近的研究表明，机械激活的Piezo1阳离子通道的功能获得性突变与脱水性红细胞疾病干细胞症有关，暗示了机械转导在红细胞体积调节中的作用。然而，这些突变导致RBC脱水的机制尚不清楚。在这项研究中，我们表明，红细胞表现出强大的钙离子进入响应机械拉伸，这种进入依赖于Piezo1的表达。此外，血细胞特异性Piezo1条件性基因敲除小鼠的RBC水化过度，在体外和体内都表现出脆性增加。最后，我们表明，Yoda1，Piezo1的化学激活剂，通过下游激活KCa3.1 Gardos通道，导致钙内流和随后的红细胞脱水，直接涉及Piezo1信号在红细胞体积控制。因此，机械激活的Piezo1在RBC体积稳态中起着至关重要的作用。DOI：http://dx.doi.org/10.7554/eLife.07370.001在我们的身体内，细胞和组织不断地被周围环境推拉。然后这些机械力被细胞转化为电信号或化学信号。这个过程对于许多生物结构（如血管）的正确发育至关重要，也是我们触觉和听觉的关键部分。在2010年，研究人员发现了一组离子通道蛋白质嵌入在细胞膜中，当施加力时，它们会打开，允许钙和其他离子进入细胞。离子的这种运动产生细胞对所施加的力的电响应。然而，人们对这些“压电”离子通道的作用知之甚少。红细胞在通过狭窄的血管时会受到很大的力。在一种称为干细胞症的疾病中，红细胞严重脱水并萎缩。2013年，研究人员发现，患有这种疾病的患者在编码Piezo1蛋白的基因中存在突变：Piezo蛋白也与胚胎血管发育有关。这表明Piezo1可以调节红细胞的体积。Cahalan，Lukacs et al.包括2010年和2013年研究的一些研究人员，现在已经更详细地研究了Piezo1在红细胞中的作用。对小鼠的红细胞施加强力，导致钙通过Piezo1通道迅速进入细胞。Cahalan、Lukacs等人随后从红细胞中删除了Piezo 1基因。这使得细胞比正常细胞更大，更脆弱，因为它们含有太多的水。为了研究Piezo1如何调节水含量，细胞被一种名为Yoda 1的化合物处理。该化合物在Syeda等人的另一项研究中显示可激活Piezo1通道。激活Piezo1也会导致第二种类型的离子通道打开，从而允许钾离子和水分子离开细胞。这导致细胞脱水。这项工作提出了压电蛋白参与红细胞体积改变的其他疾病的可能性。特别是，许多人认为Piezo1可能与镰状细胞病有关，现在可以使用本研究中描述的工具来测试这种可能性。DOI：http://dx.doi.org/10.7554/eLife.07370.002网站
Red blood cells (RBCs) experience significant mechanical forces while recirculating, but the consequences of these forces are not fully understood. Recent work has shown that gain-of-function mutations in mechanically activated Piezo1 cation channels are associated with the dehydrating RBC disease xerocytosis, implicating a role of mechanotransduction in RBC volume regulation. However, the mechanisms by which these mutations result in RBC dehydration are unknown. In this study, we show that RBCs exhibit robust calcium entry in response to mechanical stretch and that this entry is dependent on Piezo1 expression. Furthermore, RBCs from blood-cell-specific Piezo1 conditional knockout mice are overhydrated and exhibit increased fragility both in vitro and in vivo. Finally, we show that Yoda1, a chemical activator of Piezo1, causes calcium influx and subsequent dehydration of RBCs via downstream activation of the KCa3.1 Gardos channel, directly implicating Piezo1 signaling in RBC volume control. Therefore, mechanically activated Piezo1 plays an essential role in RBC volume homeostasis. DOI: http://dx.doi.org/10.7554/eLife.07370.001 Within our bodies, cells and tissues are constantly being pushed and pulled by their surrounding environment. These mechanical forces are then transformed into electrical or chemical signals by cells. This process is crucial for many biological structures, such as blood vessels, to develop correctly, and is also a key part of our senses of touch and hearing. In 2010, researchers discovered a group of ion channels—proteins embedded in the membrane that surrounds a cell—that open up when a force is applied and allow calcium and other ions to enter the cell. This movement of ions generates the electrical response of the cell to the applied force. However, not much is known about the roles of these ‘Piezo’ ion channels. Red blood cells experience significant forces when they pass through narrow blood vessels. In a disease called xerocytosis, the red blood cells become severely dehydrated and shrink. In 2013, researchers discovered that patients with this disease have mutations in the gene that codes for the Piezo1 protein: a Piezo protein that has also been linked to a role in blood vessel development in embryos. This suggested that Piezo1 may regulate the volume of red blood cells. Cahalan, Lukacs et al.—including some of the researchers who worked on the 2010 and 2013 studies—have now investigated the role of Piezo1 in red blood cells in more detail. Applying strong forces to red blood cells from mice caused calcium to rapidly enter cells through Piezo1 channels. Cahalan, Lukacs et al. then deleted the Piezo1 gene from red blood cells. This made the cells larger and more fragile than normal cells because they contained too much water. To investigate how Piezo1 regulates water content, the cells were treated with a chemical compound called Yoda1. This compound was shown in a separate study by Syeda et al. to activate Piezo1 channels. Activating Piezo1 caused a second type of ion channel to open up as well, which allowed potassium ions and water molecules to leave the cell. This resulted in the cell becoming dehydrated. This work raises the possibility that Piezo proteins are involved in other diseases where red blood cell volume is altered. In particular, many believe that Piezo1 may be involved in sickle cell disease, a possibility that can now be tested using the tools described in this study. DOI: http://dx.doi.org/10.7554/eLife.07370.002