An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice
An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice
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DOI：
10.1172/jci32312
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发表时间：
2007-11-01
影响因子：
15.9
通讯作者：
Nieswandt, Bernhard
中科院分区：
文献类型：
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作者：
Grosse, Johannes;Braun, Attila;Nieswandt, Bernhard
细胞质Ca2+水平的变化调节了几乎所有细胞的各种基本细胞功能。在不可兴奋的细胞中，Ca2+进入的主要途径包括受体介导的细胞内Ca2+储存的消耗，随后是质膜中储存操作的钙通道的激活。我们已经建立了一个小鼠系，表达基质相互作用分子1 （Stim1）的激活EF手基元突变体，这是一种内质网受体，最近被发现是负责激活T细胞中Ca2+释放激活（CRAC）通道的Ca2+传感器，其在哺乳动物生理学中的功能尚不清楚。表达突变Stim1的小鼠有大量血小板减少症和相关的出血性疾病。血小板中基底细胞内Ca2+水平升高，导致预激活状态，对免疫受体酪氨酸激活基元偶联激动剂选择性无反应，血小板消耗增加。相反，基础Ca2+水平，而不是受体介导的反应，在突变T细胞中受到影响。这些发现确定Stim1是血小板功能的中心调节因子，并提示CRAC复合物的细胞类型特异性激活或组成。
Changes in cytoplasmic Ca2+ levels regulate a variety of fundamental cellular functions in virtually all cells. in nonexcitable cells, a major pathway of Ca2+ entry involves receptor-mediated depletion of intracellular Ca2+ stores followed by the activation of store-operated calcium channels in the plasma membrane. We have established a mouse line expressing an activating EF hand motif mutant of stromal interaction molecule 1 (Stim1), an ER receptor recently identified as the Ca2+ sensor responsible for activation of Ca2+ release activated (CRAC) channels in T cells, whose function in mammalian physiology is not well understood. Mice expressing mutant Stim1 had macrothrombocytopenia and an associated bleeding disorder. Basal intracellular Ca2+ levels were increased in platelets, which resulted in a preactivation state, a selective unresponsiveness-to immunoreceptor tyrosine activation motif-coupled agonists, and increased platelet consumption. In contrast, basal Ca2+ levels, but not receptor-mediated responses, were affected in mutant T cells. These findings identify Stim1 as a central regulator of platelet function and suggest a cell type-specific activation or composition of the CRAC complex.