Differential regulation of Rho and Rac through heterotrimeric G-proteins and cyclic nucleotides.
Differential regulation of Rho and Rac through heterotrimeric G-proteins and cyclic nucleotides.
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DOI：
10.1074/jbc.m104442200
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发表时间：
2001-12-21
影响因子：
4.8
通讯作者：
Offermanns, S
中科院分区：
文献类型：
--
作者：
Gratacap, MP;Payrastre, B;Offermanns, S
使用血小板研究 Rho 和 Rac 通过 G 蛋白偶联受体的激活及其受环核苷酸的调节。血栓素 A(2) (TXA(2)) 模拟物 U46619 快速激活两种小 GTP 酶，独立于整合素 α (IIb)β (3) 激活。 U46619 导致 G(12)/G(13) 和 G(q) 激活，不会在 G α (q) 缺陷血小板中诱导 Rac 激活，但能够激活 Rho，刺激肌动蛋白聚合和磷脂酰肌醇 4,5-二磷酸形成，并诱导形状变化。野生型血小板中 U46619 对 Rac 的激活可以通过细胞内 Ca2+ 的螯合来阻断，并且对腺苷三磷酸双磷酸酶和 AR-C69931MX（Gi 偶联 ADP 受体的拮抗剂）部分敏感。 Cyclic AMP 完全阻断血小板功能，抑制 U46619 诱导的 Gq 和 G(12)/G(13) 以及 Rac 和 Rho 的激活。相比之下，cGMP 对血小板形状变化没有影响，仅阻断 G(q) 和 Rac 的激活。这些数据表明 Rho 和 Rac 通过异源三聚体 G 蛋白进行差异调节。 G(12)/G(13)介导的Rho激活参与形状改变反应，而Rac通过Gq激活并且不是形状改变所必需的。环 AMP 和 cGMP 至少部分通过 TXA2 受体对单个 G 蛋白的调节产生选择性影响，从而差异性地干扰 U46619 诱导的 Rho 和 Rac 激活。
Platelets were used to study the activation of Rho and Rac through G-protein-coupled receptors and its regulation by cyclic nucleotides. The thromboxane A(2) (TXA(2)) mimetic U46619 rapidly activated both small GTPases independently of integrin alpha (IIb)beta (3) activation. U46619, which leads to the activation of G(12)/G(13) and G(q) did not induce Rac activation in G alpha (q)-deficient platelets but was able to activate Rho, to stimulate actin polymerization and phosphatidylinositol 4,5-bisphosphate formation, and to induce shape change. Rac activation by U46619 in wild-type platelets could be blocked by chelation of intracellular Ca2+ and was partially sensitive to apyrase and AR-C69931MX an antagonist of the Gi-coupled ADP receptor. Cyclic AMP, which completely blocks platelet function, inhibited the U46619-induced activation of Gq and G(12)/G(13) as well as of Rac and Rho. In contrast, cGMP, which has no effect on platelet shape change blocked only activation of G(q) and Rac. These data demonstrate that Rho and Rac are differentially regulated through heterotrimeric G-proteins. The G(12)/G(13)-mediated Rho activation is involved in the shape change response, whereas Rac is activated through Gq and is not required for shape change. Cyclic AMP and cGMP differentially interfere with U46619-induced Rho and Rac activation at least in part by selective effects on the regulation of individual G-proteins through the TXA2 receptor.