血小板
血小板活化
化学
G蛋白偶联受体
细胞生物学
受体
信号转导
同源性脱敏
血栓素受体
蛋白酶激活受体
磷酸化
生物化学
兴奋剂
生物
凝血酶
免疫学
作者
Carl Högberg,Olof Gidlöf,Chanyuan Tan,Sven Svensson,Jenny Nilsson‐Öhman,David Erlinge,Björn Olde
标识
DOI:10.1111/j.1538-7836.2010.04158.x
摘要
The citric cycle intermediate succinate has recently been identified as a ligand for the G-protein-coupled receptor (GPCR) SUCNR1. We have previously found that this receptor is one of the most highly expressed GPCRs in human platelets.The aim of this study was to investigate the role of SUCNR1 in platelet aggregation and to explore the signaling pathways of this receptor in platelets.Using real-time-PCR, we demonstrated that SUCNR1 is expressed in human platelets at a level corresponding to that of the P2Y(1) receptor. Light transmission aggregation experiments showed dose-dependent aggregation induced by succinate, reaching a maximum response at 0.5 mM. The effect of succinate on platelet aggregation was confirmed with flow cytometry, showing increased surface expression of activated glycoprotein IIb-IIIa and P-selectin. Intracellular SUCNR1 signaling was found to result in decreased cAMP levels, Akt phosphorylation mediated by phosphoinositide 3-kinase-β activation, and receptor desensitization. Furthermore, succinate-induced platelet aggregation was demonstrated to depend on Src, generation of thromboxane A(2), and ATP release. Platelet SUCNR1 is subject to desensitization through both homologous and heterologous mechanisms. In addition, the P2Y(12) receptor inhibitor ticagrelor completely prevented platelet aggregation induced by succinate.Our experiments show that succinate induces full aggregation of human platelets via SUCNR1. Succinate-induced platelet aggregation depends on thromboxane A(2) generation, ATP release, and P2Y(12) activation.
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