Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure
Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure
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DOI：
10.1038/nm958
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发表时间：
2003-12-01
期刊：
影响因子：
82.9
通讯作者：
Mendelsohn, ME
中科院分区：
文献类型：
--
作者：
Tang, M;Wang, G;Mendelsohn, ME
一氧化氮（NO）通过激活cGMP依赖性蛋白激酶I-α（PKGI-α）抑制血管收缩，这导致肌球蛋白轻链（MLC）的去磷酸化和血管平滑肌松弛。在这里，我们表明PKGI-α通过直接激活G蛋白信号传导调节因子-2（RGS-2）减弱凝血酶受体蛋白酶激活受体-1（PAR-1）的信号传导。NO供体和cGMP引起cGMP介导的PAR-1抑制和RGS-2膜定位。PKGI-α直接结合并磷酸化RGS-2，这显著增加G（q）的GT3活性，终止PAR-1信号传导。RGS-2-PKGI-α相互作用的破坏逆转了硝基血管扩张剂和cGMP对PAR-1信号传导的抑制。Rgs2（-/-）小鼠出现明显的高血压，并且它们的血管显示出增强的收缩和降低的cGMP介导的舒张。因此，PKGI-α与RGS-2结合、磷酸化并激活RGS-2，减弱受体介导的血管收缩。我们的研究表明，RGS-2是正常血管功能和血压所必需的，是治疗高血压的新药开发靶点。
Nitric oxide (NO) inhibits vascular contraction by activating cGMP- dependent protein kinase I-alpha (PKGI-alpha), which causes dephosphorylation of myosin light chain (MLC) and vascular smooth muscle relaxation. Here we show that PKGI-alpha attenuates signaling by the thrombin receptor protease- activated receptor- 1 (PAR- 1) through direct activation of regulator of G- protein signaling- 2 (RGS- 2). NO donors and cGMP cause cGMP- mediated inhibition of PAR- 1 and membrane localization of RGS- 2. PKGI-alpha binds directly to and phosphorylates RGS- 2, which significantly increases GTPase activity of G(q), terminating PAR- 1 signaling. Disruption of the RGS- 2- PKGI-alpha interaction reverses inhibition of PAR- 1 signaling by nitrovasodilators and cGMP. Rgs2(-/-) mice develop marked hypertension, and their blood vessels show enhanced contraction and decreased cGMP-mediated relaxation. Thus, PKGI-alpha binds to, phosphorylates and activates RGS- 2, attenuating receptor- mediated vascular contraction. Our study shows that RGS- 2 is required for normal vascular function and blood pressure and is a new drug development target for hypertension.