R93W mutation in Orai1 causes impaired calcium influx in platelets
R93W mutation in Orai1 causes impaired calcium influx in platelets
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DOI：
10.1182/blood-2008-08-174516
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发表时间：
2009-01-15
期刊：
影响因子：
20.3
通讯作者：
Feske, Stefan
中科院分区：
文献类型：
--
作者：
Bergmeier, Wolfgang;Oh-hora, Masatsugu;Feske, Stefan
许多非兴奋性细胞的胞内Ca（2+）浓度受钙库释放和钙库操纵的钙内流（SOCE）的调节。在血小板中，STIM 1最近被确定为在内质网中表达的主要钙传感器。为了评估SOC通道部分Orai 1在血小板SOCE中的作用，我们产生了仅在血细胞中表达突变的无活性形式的Orai 1的小鼠（Orai 1（R93 W））。表达Orai 1 R93 W的血小板的特征是SOCE显著降低和[Ca（2+）]（i）激动剂诱导的增加受损。Orai 1（R93 W）血小板表现出降低整合素活化和受损的脱粒时，在静态条件下低浓度的激动剂刺激。然而，这种缺陷并没有显著影响Orai 1（R93 W）血小板在离体动脉血流条件下聚集或粘附于胶原蛋白的能力。相反，这些粘附的Orai 1（R93 W）血小板在表面磷脂酰丝氨酸暴露方面存在缺陷，表明Orai 1对血小板的促凝血反应至关重要，而不是对其他Ca（2+）依赖性细胞反应至关重要。（血。2009; 113：675-678）
The intracellular Ca(2+) concentration of many nonexcitable cells is regulated by calcium store release and store-operated calcium entry (SOCE). In platelets, STIM1 was recently identified as the main calcium sensor expressed in the endoplasmic reticulum. To evaluate the role of the SOC channel moiety, Orai1, in platelet SOCE, we generated mice expressing a mutated, inactive form of Orai1 in blood cells only (Orai1(R93W)). Platelets expressing Orai1R93W were characterized by markedly reduced SOCE and impaired agonist-induced increases in [Ca(2+)](i). Orai1(R93W) platelets showed reduced integrin activation and impaired degranulation when stimulated with low agonist concentrations under static conditions. This defect, however, did not significantly affect the ability of Orai1(R93W) platelets to aggregate or to adhere to collagen under arterial flow conditions ex vivo. In contrast, these adherent Orai1(R93W) platelets were defective in surface phosphatidylserine exposure, suggesting that Orai1 is crucial for the platelets' procoagulant response rather than for other Ca(2+)- dependent cellular responses. (Blood. 2009; 113: 675-678)