Potentiation of thromboxane A2-induced platelet secretion by Gi signaling through the phosphoinositide-3 kinase pathway
Potentiation of thromboxane A2-induced platelet secretion by Gi signaling through the phosphoinositide-3 kinase pathway
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DOI：
10.1055/s-0037-1615690
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发表时间：
2001-02-01
影响因子：
6.7
通讯作者：
Kunapuli, SP
中科院分区：
文献类型：
--
作者：
Dangelmaier, C;Jin, JG;Kunapuli, SP
血小板活化导致形状改变、聚集、血栓素A（2）的产生和颗粒内容物的释放。我们最近证明分泌的ADP对于血栓素A（2）诱导的血小板聚集是必需的（J.Biol.Chem.274：29108-29114，1999）。本研究的目的是研究分泌型ADP与P2受体亚型相互作用在血小板分泌中的作用。血栓素A（2）模拟物U46619诱导的血小板分泌不受腺苷-3 '-磷酸-5'-磷酸的影响。P2 Y1受体选择性拮抗剂。然而，AR-C66096是P2 T（AC）受体的选择性拮抗剂。抑制U46619诱导的血小板分泌，表明Gi信号在血小板分泌中的重要作用。选择性激活P2 T（AC）受体或α（2A）肾上腺素能受体不会引起血小板分泌，但增强U46619诱导的血小板分泌。纤维蛋白原受体拮抗剂SC 57101不能抑制血小板分泌，表明血小板分泌不需要由外向内的信号传导。由于G（i）信号通过抑制腺苷酸环化酶导致基础cAMP水平降低，我们研究了这是否是增强血小板分泌的信号事件。腺苷酸环化酶抑制剂SQ 22536或双脱氧腺苷未能增强U46619诱导的初级血小板分泌，表明cAMP水平的降低并不直接促进血小板分泌。Wortmannin是一种PI-3激酶的选择性抑制剂，当它仅由Gq介导时，对U46619诱导的血小板分泌有最低程度的抑制作用，但对G（i）信号的增强作用有显著的消除作用。我们的结论是，通过P2 T（AC）受体分泌的ADP信号通过PI-3激酶途径引起血小板分泌的正反馈。
Platelet activation results in shape change, aggregation, generation of thromboxane A(2), and release of granule contents. We have recently demonstrated that secreted ADP is essential for thromboxane A(2)-induced platelet aggregation (J. Biol. Chem. 274: 29108-29114, 1999). The aim of this study was to investigate the role of secreted ADP interacting at P2 receptor subtypes in platelet secretion. Platelet secretion induced by the thromboxane A(2) mimetic U46619 was unaffected by adenosine-3'phosphate-5'-phosphate. a P2Y1 receptor selective antagonist. However, AR-C66096, a selective antagonist of the P2T(AC) receptor. inhibited U46619-induced platelet secretion, indicating an important role for Gi signaling in platelet secretion. Selective activation of either the P2T(AC) receptor or the alpha (2A) adrenergic receptor did not cause platelet secretion, but potentiated U46619-induced platelet secretion. SC57101, a fibrinogen receptor antagonist, failed to inhibit platelet secretion, demonstrating that outside-in signaling was not required for platelet secretion. Since G(i) signaling results in reduction of basal cAMP levels through inhibition of adenylyl cyclase, we investigated whether this is the signaling event that potentiates platelet secretion. SQ22536 or dideoxyadenosine, inhibitors of adenylyl cyclase, failed to potentiate U46619-induced primary platelet secretion, indicating that reduction in cAMP levels does not directly contribute to platelet secretion. Wortmannin, a selective inhibitor of PI-3 kinase, minimally inhibited U46619-induced platelet secretion when it was solely mediated by Gq, but dramatically ablated the potentiation of G(i) signaling. We conclude that signaling through the P2T(AC) receptor by secreted ADP causes positive feedback on platelet secretion through a PI-3 kinase pathway.