Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation
Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation
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DOI：
10.1182/blood-2008-07-171611
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发表时间：
2009-02-26
期刊：
影响因子：
20.3
通讯作者：
Nieswandt, Bernhard
中科院分区：
文献类型：
--
作者：
Braun, Attila;Varga-Szabo, David;Nieswandt, Bernhard
血管损伤部位的血小板活化和聚集是主要止血所必需的，但也是心肌梗死和卒中的主要病理机制。[Ca 2 +]（i）的变化是血小板活化的中心步骤。在非兴奋性细胞中，受体介导的细胞内Ca 2+储存的耗竭通过储存操纵的钙（SOC）通道触发Ca 2+进入。STIM 1已被鉴定为内质网（ER）驻留的Ca 2+传感器，其调节免疫细胞和血小板中的钙库操作的钙进入（SOCE），但血小板SOC通道的身份仍然难以捉摸。Orai 1（CRACM 1）是最近在T细胞和肥大细胞中发现的SOC（CRAC）通道，但其在哺乳动物生理学中的作用尚不清楚。在这里，我们报告说，Orai 1是强烈表达在人类和小鼠血小板。为了测试其在凝血中的作用，我们产生了Orai 1缺陷小鼠，发现它们的血小板显示严重缺陷的SOCE，激动剂诱导的Ca 2+反应，以及体外流动下受损的活化和血栓形成。作为直接结果，小鼠中Orai 1缺乏导致对肺血栓栓塞、动脉血栓形成和缺血性脑梗死的抵抗，但仅轻度出血时间延长。这些结果确立了Orai 1作为长期寻找的血小板SOC通道和缺血性心血管和脑血管事件的关键介质。（血。2009; 113：2056-2063）
Platelet activation and aggregation at sites of vascular injury are essential for primary hemostasis, but are also major pathomechanisms underlying myocardial infarction and stroke. Changes in [Ca2+](i) are a central step in platelet activation. In nonexcitable cells, receptor-mediated depletion of intracellular Ca2+ stores triggers Ca2+ entry through store-operated calcium (SOC) channels. STIM1 has been identified as an endoplasmic reticulum (ER)-resident Ca2+ sensor that regulates store-operated calcium entry (SOCE) in immune cells and platelets, but the identity of the platelet SOC channel has remained elusive. Orai1 (CRACM1) is the recently discovered SOC (CRAC) channel in T cells and mast cells but its role in mammalian physiology is unknown. Here we report that Orai1 is strongly expressed in human and mouse platelets. To test its role in blood clotting, we generated Orai1-deficient mice and found that their platelets display severely defective SOCE, agonist-induced Ca2+ responses, and impaired activation and thrombus formation under flow in vitro. As a direct consequence, Orai1 deficiency in mice results in resistance to pulmonary thromboembolism, arterial thrombosis, and ischemic brain infarction, but only mild bleeding time prolongation. These results establish Orai1 as the long-sought platelet SOC channel and a crucial mediator of ischemic cardiovascular and cerebrovascular events. (Blood. 2009; 113: 2056-2063)