Platelet hyperreactivity and a prothrombotic phenotype in mice with a gain-of-function mutation in phospholipase Cγ2
Platelet hyperreactivity and a prothrombotic phenotype in mice with a gain-of-function mutation in phospholipase Cγ2
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DOI：
10.1111/j.1538-7836.2010.03838.x
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发表时间：
2010-06-01
影响因子：
10.4
通讯作者：
Nieswandt, B.
中科院分区：
文献类型：
--
作者：
Elvers, M.;Pozgaj, R.;Nieswandt, B.
背景资料：激动剂诱导的血小板活化涉及导致磷脂酶C（PLC）β或PLC γ 2活化的不同信号传导途径。激活的PLC产生肌醇1，4，5-三磷酸和甘油二酯，其分别触发Ca 2+动员和蛋白激酶C的激活。PLC β在可溶性激动剂的Gq偶联受体下游被激活，只有很短的相互作用时间。欠血相比之下，PLC γ 2在与固定化配体如胶原受体糖蛋白（GP）VI或活化整联蛋白相互作用的受体下游被活化。目的和方法：我们推测，PLC γ 2活性可能是持续的，但次最大的信号控制相对缓慢的血小板反应优化。为了验证这一假设，我们分析了Plcg 2基因中功能获得性突变（Plcg 2（Ali 5/+））杂合小鼠的血小板。结果如下：Plcg 2（Ali 5/+）血小板在GPVI或C-型凝集素样受体-2刺激后表现出增强的Ca 2+动员、整合素活化、颗粒分泌和磷脂酰丝氨酸暴露。此外，整合素α（IIb）β（3）由外向内的信号传导在突变血小板中显著增强，如在不同基质上加速扩散和更快的血块收缩所示。这些缺陷转化为在体外流动下胶原上几乎无限制的血栓形成和体内促血栓形成表型。结论：这些结果表明，PLC γ 2的酶活性受到严格调节，以确保在血管损伤部位有效但有限的血小板活化。
Background: Agonist-induced platelet activation involves different signaling pathways leading to the activation of phospholipase C (PLC) beta or PLC gamma 2. Activated PLC produces inositol 1,4,5-trisphosphate and diacylglycerol, which trigger Ca2+ mobilization and the activation of protein kinase C, respectively. PLC beta is activated downstream of Gq-coupled receptors for soluble agonists with only short interaction times in. owing blood. In contrast, PLC gamma 2 becomes activated downstream of receptors that interact with immobilized ligands such as the collagen receptor glycoprotein (GP) VI or activated integrins. Objective and methods: We speculated that PLC gamma 2 activity might be optimized for sustained but submaximal signaling to control relatively slow platelet responses. To test this hypothesis, we analyzed platelets from mice heterozygous for a gain-of-function mutation in the Plcg2 gene (Plcg2(Ali5/+)). Results: Plcg2(Ali5/+) platelets showed enhanced Ca2+ mobilization, integrin activation, granule secretion and phosphatidylserine exposure upon GPVI or C-type lectin-like receptor-2 stimulation. Furthermore, integrin alpha(IIb)beta(3) outside-in signaling was markedly enhanced in the mutant platelets, as shown by accelerated spreading on different matrices and faster clot retraction. These defects translated into virtually unlimited thrombus formation on collagen under flow in vitro and a prothrombotic phenotype in vivo. Conclusions: These results demonstrate that the enzymatic activity of PLC gamma 2 is tightly regulated to ensure efficient but limited platelet activation at sites of vascular injury.