当前位置: X-MOL 学术Sci. Signal. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Ca2+ waves coordinate purinergic receptor-evoked integrin activation and polarization.
Science Signaling ( IF 7.3 ) Pub Date : 2020-01-21 , DOI: 10.1126/scisignal.aav7354
Alexander P Bye 1 , Jonathan M Gibbins 1 , Martyn P Mahaut-Smith 2
Affiliation  

Cells sense extracellular nucleotides through the P2Y class of purinergic G protein-coupled receptors (GPCRs), which stimulate integrin activation through signaling events, including intracellular Ca2+ mobilization. We investigated the relationship between P2Y-stimulated repetitive Ca2+ waves and fibrinogen binding to the platelet integrin αIIbβ3 (GPIIb/IIIa) through confocal fluorescence imaging of primary rat megakaryocytes. Costimulation of the receptors P2Y1 and P2Y12 generated a series of Ca2+ transients that each induced a rapid, discrete increase in fibrinogen binding. The peak and net increase of individual fibrinogen binding events correlated with the Ca2+ transient amplitude and frequency, respectively. Using BAPTA loading and selective receptor antagonists, we found that Ca2+ mobilization downstream of P2Y1 was essential for ADP-evoked fibrinogen binding, whereas P2Y12 and the kinase PI3K were also required for αIIbβ3 activation and enhanced the number of Ca2+ transients. ADP-evoked fibrinogen binding was initially uniform over the cell periphery but subsequently redistributed with a polarity that correlated with the direction of the Ca2+ waves. Polarization of αIIbβ3 may be mediated by the actin cytoskeleton, because surface-bound fibrinogen is highly immobile, and its motility was enhanced by cytoskeletal disruption. In conclusion, spatial and temporal patterns of Ca2+ increase enable fine control of αIIbβ3 activation after cellular stimulation. P2Y1-stimulated Ca2+ transients coupled to αIIbβ3 activation only in the context of P2Y12 coactivation, thereby providing an additional temporal mechanism of synergy between these Gq- and Gi-coupled GPCRs.

中文翻译:

Ca2 +波协调嘌呤能受体诱发的整联蛋白激活和极化。

细胞通过嘌呤能G蛋白偶联受体(GPCR)的P2Y类感知细胞外核苷酸,其通过信号传递事件(包括细胞内Ca2 +动员)刺激整联蛋白激活。我们通过共聚焦荧光成像对原代大鼠巨核细胞进行了P2Y刺激的重复Ca2 +波与血纤蛋白原与血小板整合素αIIbβ3(GPIIb / IIIa)结合的关系的研究。受体P2Y1和P2Y12的共刺激产生一系列Ca2 +瞬变,每个瞬变都引起血纤蛋白原结合的快速,离散增加。单个纤维蛋白原结合事件的峰值和净增加分别与Ca2 +瞬时振幅和频率相关。使用BAPTA负载和选择性受体拮抗剂,我们发现,P2Y1下游的Ca2 +动员对于ADP诱发的纤维蛋白原结合至关重要,而αIIbβ3激活也需要P2Y12和激酶PI3K,并增加了Ca2 +瞬态的数量。ADP引起的纤维蛋白原结合在细胞周围最初是均匀的,但随后以与Ca2 +波的方向相关的极性重新分布。αIIbβ3的极化可能是由肌动蛋白的细胞骨架介导的,因为表面结合的纤维蛋白原是高度固定的,并且其运动性由于细胞骨架的破坏而增强。总之,Ca2 +的时空分​​布增加使得能够在细胞刺激后精确控制αIIbβ3的活化。仅在P2Y12共激活的情况下,P2Y1刺激的Ca2 +瞬变与αIIbβ3激活耦合,
更新日期:2020-01-22
down
wechat
bug