Department of Vascular and Endovascular Surgery, Experimental Vascular Medicine, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
Int J Mol Sci. 2022 May 2;23(9):5059. doi: 10.3390/ijms23095059.
Pannexin-1 (PANX1) is a transmembrane protein that forms ion channels as hexamers on the plasma membrane. Electrophysiological studies prove that PANX1 has a high conductance for adenosine triphosphate (ATP), which plays an important role as a signal molecule in platelet activation. Recently, it was shown that PANX1 channels modulate platelet functions. To date, it remains unclear how PANX1 channels are activated and which signaling mechanisms are responsible for impaired hemostasis and thrombosis. Analysis of PANX1 phosphorylation at Tyr and Tyr, and the impact on platelet activation and thrombus formation using genetically modified platelets or pharmacological inhibitors. Platelet activation via immunoreceptor tyrosine-based activation motif (ITAM) coupled, G Protein-Coupled Receptors (GPCR) and thromboxane receptor (TP)-mediated signaling pathways led to increased PANX1 phosphorylation at Tyr and Tyr. We identified the Src-GPVI signaling axes as the main pathway inducing PANX1 activation, while PKC and Akt play a minor role. PANX1 channels function as ATP release channels in platelets to support arterial thrombus formation. PANX1 activation is regulated by phosphorylation at Tyr and Tyr following platelet activation. These results suggest an important role of PANX1 in hemostasis and thrombosis by releasing extracellular ATP to support thrombus formation.
连接蛋白-1（PANX1）是一种跨膜蛋白，在质膜上以六聚体的形式形成离子通道。电生理学研究证明，PANX1 对三磷酸腺苷（ATP）具有高传导性，ATP 作为血小板激活的信号分子发挥重要作用。最近，研究表明 PANX1 通道调节血小板功能。迄今为止，尚不清楚 PANX1 通道如何被激活，以及哪些信号机制负责止血和血栓形成受损。使用基因修饰血小板或药理学抑制剂分析 Tyr 和 Tyr 上的 PANX1 磷酸化及其对血小板激活和血栓形成的影响。通过免疫受体酪氨酸激活基序（ITAM）偶联的 G 蛋白偶联受体（GPCR）和血栓烷受体（TP）介导的信号通路导致 Tyr 和 Tyr 上的 PANX1 磷酸化增加。我们确定 Src-GPVI 信号轴作为诱导 PANX1 激活的主要途径，而 PKC 和 Akt 则起次要作用。PANX1 通道在血小板中作为 ATP 释放通道发挥作用，以支持动脉血栓形成。PANX1 的激活受血小板激活后 Tyr 和 Tyr 上的磷酸化调节。这些结果表明，通过释放细胞外 ATP 来支持血栓形成，PANX1 在止血和血栓形成中发挥重要作用。
