Costimulation of Gi- and G12/G13-mediated signaling pathways induces integrin αIIbβ3 activation in platelets
Costimulation of Gi- and G12/G13-mediated signaling pathways induces integrin αIIbβ3 activation in platelets
复制标题
DOI：
10.1074/jbc.m207256200
复制
发表时间：
2002-10-18
影响因子：
4.8
通讯作者：
Offermanns, S
中科院分区：
文献类型：
--
作者：
Nieswandt, B;Schulte, V;Offermanns, S
血小板活化是由多种刺激引起的复杂过程，这些刺激协同作用以确保血管损伤部位快速形成血小板栓塞。我们在这里表明，纤维状胶原蛋白在受损的血管壁处启动血小板活化，仅直接活化悬浮液中的一小部分血小板，而大多数血小板被胶原活化的血小板释放的介质激活。在缺乏 Galpha(q) 的血小板中，整合素 α(IIb)beta(3) 的激活对血栓素 A(2) (TXA(2))、凝血酶或 ADP 等多种介质没有反应，高浓度的胶原蛋白能够诱导聚集，这种作用可以被 TXA(2) 或 P2Y(12) 受体拮抗剂阻断。单独激活 TXA(2) 或 P2Y(12) 受体（在 Galpha(q) 缺陷的血小板中分别与 G(12)/G(13) 和 G(i) 偶联）不会诱导血小板整合素激活或聚集。然而，两种受体的同时激活导致不可逆的整合素α(IIb)β(3)介导的Galpha(q)缺陷血小板聚集。因此，G(12)/G(13)和G(i)介导的信号通路的激活足以诱导整合素α(IIb)β(3)激活。尽管 G(q) 介导的信号传导在血小板激活中发挥重要作用，但它并不是整合素 α(IIb)β(3) 激活所严格必需的。这表明通过G蛋白偶联受体有效诱导血小板聚集是由涉及G(q)和G(i)以及G(12)/G(13)的各种汇聚G蛋白介导的信号通路介导的整合反应。
Platelet activation is a complex process induced by a variety of stimuli, which act in concert to ensure the rapid formation of a platelet plug at places of vascular injury. We show here that fibrillar collagen, which initiates platelet activation at the damaged vessel wall, activates only a small fraction of platelets in suspension directly, whereas the majority of platelets becomes activated by mediators released from collagen-activated platelets. In Galpha(q)-deficient platelets that do not respond with activation of integrin alpha(IIb)beta(3) to a variety of mediators like thromboxane A(2) (TXA(2)), thrombin, or ADP, collagen at high concentrations was able to induce aggregation, an effect that could be blocked by antagonists of the TXA(2) or P2Y(12) receptors. The activation of TXA(2) or P2Y(12) receptors alone, which in Galpha(q)-deficient platelets couple to G(12)/G(13) and G(i), respectively, did not induce platelet integrin activation or aggregation. However, concomitant activation of both receptors resulted in irreversible integrin alpha(IIb)beta(3)-mediated aggregation of Galpha(q)-deficient platelets. Thus, the activation of G(12)/G(13)- and G(i)-mediated signaling pathways is sufficient to induce integrin alpha(IIb)beta(3) activation. Although G(q)-mediated signaling plays an important role in platelet activation, it is not strictly required for the activation of integrin alpha(IIb)beta(3). This indicates that the efficient induction of platelet aggregation through G-protein-coupled receptors is an integrated response mediated by various converging G-protein-mediated signaling pathways involving G(q) and G(i) as well as G(12)/G(13).