Synapse Research Institute Maastricht, Koningin Emmaplein 7, 6217 KD Maastricht, The Netherlands.
Int J Mol Sci. 2022 Oct 19;23(20):12512. doi: 10.3390/ijms232012512.
Integrin αIIbβ3 activation is essential for platelet aggregation and, accordingly, for hemostasis and arterial thrombosis. The αIIbβ3 integrin is highly expressed on platelets and requires an activation step for binding to fibrinogen, fibrin or von Willebrand factor (VWF). A current model assumes that the process of integrin activation relies on actomyosin force-dependent molecular changes from a bent-closed and extended-closed to an extended-open conformation. In this paper we review the pathways that point to a functional reversibility of platelet αIIbβ3 activation and transient aggregation. Furthermore, we refer to mouse models indicating that genetic defects that lead to reversible platelet aggregation can also cause instable thrombus formation. We discuss the platelet agonists and signaling pathways that lead to a transient binding of ligands to integrin αIIbβ3. Our analysis points to the (autocrine) ADP P2Y and P2Y receptor signaling via phosphoinositide 3-kinases and Akt as principal pathways linked to reversible integrin activation. Downstream signaling events by protein kinase C, CalDAG-GEFI and Rap1b have not been linked to transient integrin activation. Insight into the functional reversibility of integrin activation pathways will help to better understand the effects of antiplatelet agents.
整合素 αIIbβ3 的激活对于血小板聚集至关重要，进而对于止血和动脉血栓形成也是如此。αIIbβ3 整合素在血小板上高度表达，并且需要激活步骤才能与纤维蛋白原、纤维蛋白或血管性血友病因子 (VWF) 结合。目前的模型假设整合素激活的过程依赖于肌动球蛋白力依赖性的分子变化，从弯曲关闭和延伸关闭到延伸开放构象。在本文中，我们回顾了指向血小板 αIIbβ3 激活和短暂聚集的功能可逆性的途径。此外，我们提到了表明导致可逆血小板聚集的遗传缺陷也可能导致不稳定血栓形成的小鼠模型。我们讨论了导致配体与整合素 αIIbβ3 短暂结合的血小板激动剂和信号通路。我们的分析指出，（自分泌）ADP P2Y 和 P2Y 受体通过磷酸肌醇 3-激酶和 Akt 信号转导是与可逆整合素激活相关的主要途径。蛋白激酶 C、CalDAG-GEFI 和 Rap1b 的下游信号事件尚未与短暂整合素激活相关联。对整合素激活途径的功能可逆性的深入了解将有助于更好地理解抗血小板药物的作用。
