Sun Der-Shan, Lo Szecheng J, Tsai Wei-Jern, Lin Chi-Hung, Yu Mei-Shiuan, Chen Yao-Fong, Chang Hsin-Hou
Institute of Human Genetics, Tzu-Chi University, Hualien 970, Taiwan, Republic of China.
J Biomed Sci. 2005 Dec;12(6):937-48. doi: 10.1007/s11373-005-9016-z. Epub 2005 Oct 14.
Phosphatidylinositol 3-kinase (PI3K) pathway is important for platelet activation. Recent studies showed that PI3K and oscillative calcium could cross talk to each other and positively regulate integrin alpha (IIb)beta3-mediated outside-in signaling. However, the mechanism of this feedback regulation remains to be further characterized. Here we found that treatments of both PI3K inhibitor wortmannin and P2Y1 inhibitor A3P5P could inhibit granular secretion in platelets. Additionally, when RGD-substrate adherent platelets were treated with the ADP scavenger apyrase to deplete the granular-released ADP, their attachments in engaging with substrates became looser and the frequency of calcium oscillation decreased. Since it is known that ADP stimulates the PI3K and calcium signal primarily through P2Y12 and P2Y1 receptors respectively, our data indicated that integrin alpha(IIb)beta3 downstream PI3K and calcium activation might be not completely coupled to integrin associated signaling complex, but in part through feedback stimulation by granular released ADP. Our data indicates the important roles of PI3K and granular released ADP in coordinating the feedback regulations in integrin alpha(IIb)beta3-mediated platelet activation.
磷脂酰肌醇3激酶（PI3K）信号通路对血小板激活至关重要。最近的研究表明，PI3K与振荡性钙可相互作用，并正向调节整合素α（IIb）β3介导的外向内信号传导。然而，这种反馈调节的机制仍有待进一步明确。在此，我们发现PI3K抑制剂渥曼青霉素和P2Y1抑制剂A3P5P均可抑制血小板中的颗粒分泌。此外，当用ADP清除剂阿糖苷酶处理RGD底物黏附的血小板以耗尽颗粒释放的ADP时，它们与底物结合的附着力变弱，钙振荡频率降低。由于已知ADP分别主要通过P2Y12和P2Y1受体刺激PI3K和钙信号，我们的数据表明，整合素α（IIb）β3下游的PI3K和钙激活可能并非完全与整合素相关信号复合物偶联，而是部分通过颗粒释放的ADP的反馈刺激实现。我们的数据表明PI3K和颗粒释放的ADP在协调整合素α（IIb）β3介导的血小板激活中的反馈调节方面发挥重要作用。
