Transient Receptor Potential Channels Function as a Coincidence Signal Detector Mediating Phosphatidylserine Exposure
Transient Receptor Potential Channels Function as a Coincidence Signal Detector Mediating Phosphatidylserine Exposure
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DOI：
10.1126/scisignal.2003701
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发表时间：
2013-06-25
影响因子：
7.3
通讯作者：
Poole, Alastair W.
中科院分区：
文献类型：
--
作者：
Harper, Matthew T.;Londono, Juan E. Camacho;Poole, Alastair W.
必须严格控制血小板聚集，以促进损伤部位的凝血，同时避免不适当的血管闭塞。凝血酶裂解并激活G(q)偶联蛋白酶激活受体，胶原相关肽激活受体糖蛋白VI，刺激血小板聚集形成血栓。这两种激动剂的同时激活协同作用，导致磷脂酰丝氨酸暴露在细胞表面，这是许多细胞类型中细胞死亡的标志。磷脂酰丝氨酸暴露对于在血小板表面产生额外的凝血酶也是必不可少的，这有助于血栓形成。我们发现凝血酶受体或糖蛋白VI单独激活都会产生钙信号，该信号在很大程度上仅依赖于存储操作的Ca2+进入。相比之下，基因敲除小鼠的血小板实验表明，这两种配体的存在激活了瞬时受体电位C（TRPC）家族TRPC3和TRPC6的非选择性阳离子通道。这些通道主要允许Na+进入，它耦合到反向模式Na+/Ca2+交换，允许钙流入，从而促进Ca2+信号和磷脂酰丝氨酸暴露。因此，TRPC通道作为巧合探测器，协调细胞对多种信号的反应，从而间接介导血小板细胞内钙浓度的增加和血栓形成前磷脂酰丝氨酸的暴露。
Blood platelet aggregation must be tightly controlled to promote clotting at injury sites but avoid inappropriate occlusion of blood vessels. Thrombin, which cleaves and activates G(q)-coupled protease-activated receptors, and collagen-related peptide, which activates the receptor glycoprotein VI, stimulate platelets to aggregate and form thrombi. Coincident activation by these two agonists synergizes, causing the exposure of phosphatidylserine on the cell surface, which is a marker of cell death in many cell types. Phosphatidylserine exposure is also essential to produce additional thrombin on platelet surfaces, which contributes to thrombosis. We found that activation of either thrombin receptors or glycoprotein VI alone produced a calcium signal that was largely dependent only on store-operated Ca2+ entry. In contrast, experiments with platelets from knockout mice showed that the presence of both ligands activated nonselective cation channels of the transient receptor potential C(TRPC) family, TRPC3 and TRPC6. These channels principally allowed entry of Na+, which coupled to reverse-mode Na+/Ca2+ exchange to allow calcium influx and thereby contribute to Ca2+ signaling and phosphatidylserine exposure. Thus, TRPC channels act as coincidence detectors to coordinate responses to multiple signals in cells, thereby indirectly mediating in platelets an increase in intracellular calcium concentrations and exposure of prothrombotic phosphatidylserine.