Stefanini Lucia, Bergmeier Wolfgang
Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK.
Department of Biochemistry and Biophysics, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
J Mol Med (Berl). 2016 Jan;94(1):13-9. doi: 10.1007/s00109-015-1346-3. Epub 2015 Oct 1.
Platelets are critical for hemostasis, i.e., the body's ability to prevent blood loss at sites of vascular injury. They patrol the vasculature in a quiescent, non-adhesive state for approximately 10 days, after which they are removed from circulation by phagocytic cells of the reticulo-endothelial system. At sites of vascular injury, they promptly shift to an activated, adhesive state required for the formation of a hemostatic plug. The small GTPase RAP1 is a critical regulator of platelet adhesiveness. Our recent studies demonstrate that the antagonistic balance between the RAP1 regulators, CalDAG-GEFI and RASA3, is critical for the modulation of platelet adhesiveness, both in circulation and at sites of vascular injury. The RAP1 activator CalDAG-GEFI responds to small changes in the cytoplasmic calcium concentration and thus provides sensitivity and speed to the activation response, essential for efficient platelet adhesion under conditions of hemodynamic shear stress. The RAP1 inhibitor RASA3 ensures that circulating platelets remain quiescent by restraining CalDAG-GEFI-dependent RAP1 activation. Upon cellular stimulation, it is turned off by P2Y12 signaling to enable sustained RAP1 activation, required for the formation of a stable hemostatic plug. This review will summarize important studies that elucidated the signaling pathways that control RAP1 activation in platelets.
血小板对于止血至关重要，即身体在血管损伤部位防止失血的能力。它们以静止、非黏附状态在脉管系统中巡逻约10天，之后被网状内皮系统的吞噬细胞从循环中清除。在血管损伤部位，它们迅速转变为形成止血栓所需的活化、黏附状态。小GTP酶RAP1是血小板黏附性的关键调节因子。我们最近的研究表明，RAP1调节因子CalDAG-GEFI和RASA3之间的拮抗平衡对于调节循环中和血管损伤部位的血小板黏附性至关重要。RAP1激活剂CalDAG-GEFI对细胞质钙浓度的微小变化做出反应，从而为激活反应提供敏感性和速度，这对于在血流动力学剪切应力条件下高效的血小板黏附至关重要。RAP1抑制剂RASA3通过抑制CalDAG-GEFI依赖的RAP1激活来确保循环中的血小板保持静止。在细胞受到刺激时，它通过P2Y12信号传导被关闭，以使稳定止血栓形成所需的RAP1持续激活。本综述将总结阐明控制血小板中RAP1激活的信号通路的重要研究。
