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A new role for Fc gamma RIIA in the potentiation of human platelet activation induced by weak stimulation

机译：FcγRIIA在弱刺激诱导的人血小板活化增强中的新作用

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The low affinity receptor for immunoglobulin G, Fc gamma RIIA, is expressed in human platelets, mediates heparin-induced thrombocytopenia and participates to platelet activation induced by von Willebrand factor. In this work, we found that stimulation of platelets with agonists acting on G-protein-coupled receptors resulted in the tyrosine phosphorylation of Fc gamma RIIA, through a mechanism involving a Re kinase. Treatment of platelets with the blocking monoclonal antibody IV3 against Fc gamma RIIA, but not with control IgG, inhibited platelet aggregation induced by TRAP1, TRAP4, the thromboxane analogue U46619, and low concentrations of thrombin. By contrast, platelet aggregation induced by high doses of thrombin was unaffected by blockade of Fc gamma RIIA. We also found that the anti-Fc gamma RIIA monoclonal antibody IV.3 inhibited pleckstrin phosphorylation and calcium mobilization induced by low, but not high, concentrations of thrombin. In addition, thrombin- or U46619-induced tyrosine phosphorylation of several substrates typically involved in Fc gamma RIIA-mediated signalling, such as Syk and PLC gamma 2, was clearly reduced by incubation with anti-Fc gamma RIIA antibody IV.3. Upon stimulation with thrombin, Fc gamma RIIA relocated in lipid rafts, and thrombin-induced tyrosine phosphorylation of Fc gamma RIIA occurred within these membrane domains. Controlled disruption of lipid rafts by depleting membrane cholesterol prevented tyrosine phosphorylation of Fc gamma RIIA and impaired platelet aggregation induced by U46619 or by low, but not high, concentrations of thrombin. These results indicate that Fc gamma RIIA can be activated in human platelets downstream G-protein-coupled receptors and suggest a novel general mechanism for the reinforcement of platelet activation induced by low concentrations of agonists. (c) 2005 Elsevier Inc. All rights reserved.
机译：免疫球蛋白G的低亲和力受体FcγRIIA在人血小板中表达，介导肝素诱导的血小板减少，并参与由von Willebrand因子诱导的血小板活化。在这项工作中，我们发现作用于G蛋白偶联受体的激动剂对血小板的刺激通过涉及Re激酶的机制导致FcγRIIA的酪氨酸磷酸化。用针对FcγRIIA的封闭性单克隆抗体IV3处理血小板，但不使用对照IgG处理，可抑制TRAP1，TRAP4，血栓烷类似物U46619和低浓度凝血酶诱导的血小板聚集。相比之下，高剂量凝血酶诱导的血小板聚集不受FcγRIIA的阻滞作用的影响。我们还发现抗-FcγRIIA单克隆抗体IV.3抑制了低浓度（但不是高浓度）的凝血酶诱导的pleckstrin磷酸化和钙动员。另外，通过与抗FcγRIIA抗体IV.3一起孵育，明显减少了通常由FcγRIIA介导的信号转导的几种底物的凝血酶或U46619诱导的酪氨酸磷酸化，例如Syk和PLCγ2。凝血酶刺激后，FcγRIIA重新定位在脂质筏中，并且凝血酶诱导的FcγRIIA酪氨酸磷酸化发生在这些膜结构域内。通过减少膜胆固醇控制脂质筏的破坏，可防止FcγRIIA的酪氨酸磷酸化和U46619或低但不高浓度的凝血酶诱导的血小板聚集受损。这些结果表明FcγRIIA可以在人血小板下游的G蛋白偶联受体中被激活，并且提出了用于增强由低浓度激动剂诱导的血小板激活的新的一般机制。 （c）2005 Elsevier Inc.保留所有权利。

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