Caveolae are required for protease-selective signaling by protease-activated receptor-1.
Caveolae are required for protease-selective signaling by protease-activated receptor-1.
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小凹是蛋白酶激活受体 1 的蛋白酶选择性信号传导所必需的。
DOI：
10.1073/pnas.0810687106
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发表时间：
2009
影响因子：
11.1
通讯作者：
Trejo,Joann
中科院分区：
文献类型：
--
作者：
Russo,Angela;Soh,UniceJK;Paing,MayM;Arora,Puneeta;Trejo,Joann
蛋白水解酶激活受体-1(PAR1)是一种G蛋白偶联受体，由蛋白水解酶唯一激活。凝血酶是一种凝血酶，通过激活PAR1诱导炎症反应和内皮屏障通透性。活化蛋白C(APC)是一种抗凝血酶，也能激活PAR1。然而，与凝血酶不同的是，APC可诱导抗炎反应，并可保护凝血酶诱导的内皮屏障功能障碍。我们发现，在PAR1缺失的内皮细胞中，凝血酶和APC信号丢失，表明PAR1是蛋白酶信号的主要效应者。为了阐明PAR1激活蛋白水解酶选择性信号的机制，我们研究了APC和凝血酶对RhoA和rac1激活的影响，RhoA和rac1是调节内皮屏障通透性的小GTP酶。凝血酶可引起强烈的RhoA信号，但不能激活rac1，而APC可显著增加rac1的激活，但不能激活RhoA信号，这与这些酶在内皮屏障完整性上的相反功能是一致的。值得注意的是，在缺乏小窝蛋白-1的细胞中，APC信号和内皮屏障保护作用被取消，而凝血酶信号保持不变。这些发现表明，小窝中PAR1的区划对于APC选择性地激活rac1和保护内皮屏障是至关重要的。我们进一步报道，APC诱导PAR1磷酸化，使内皮细胞对凝血酶信号不敏感，但促进有限的受体切割，即使在长期暴露APC后，内化和降解也可以忽略不计。因此，APC选择性信号和内皮屏障保护作用是通过小窝中PAR1的区域化和一种新的PAR1信号调节机制来介导的。
Protease-activated receptor-1 (PAR1) is a G-protein–coupled receptor uniquely activated by proteolysis. Thrombin, a coagulant protease, induces inflammatory responses and endothelial barrier permeability through the activation of PAR1. Activated protein C (APC), an anti-coagulant protease, also activates PAR1. However, unlike thrombin, APC elicits anti-inflammatory responses and protects against endothelial barrier dysfunction induced by thrombin. We found that thrombin and APC signaling were lost in PAR1-deficient endothelial cells, indicating that PAR1is the major effector of protease signaling. To delineate the mechanism responsible for protease-selective signaling by PAR1, we examined the effect of APC and thrombin on the activation of RhoA and Rac1, small GTPases that differentially regulate endothelial barrier permeability. Thrombin caused robust RhoA signaling but not Rac1 activation, whereas APC stimulated a marked increase in Rac1 activation but not RhoA signaling, consistent with the opposing functions of these proteases on endothelial barrier integrity. Strikingly, APC signaling and endothelial barrier protection effects were abolished in cells lacking caveolin-1, whereas thrombin signaling remained intact. These findings suggest that compartmentalization of PAR1in caveolae is critical for APC selective signaling to Rac1 activation and endothelial barrier protection. We further report that APC induces PAR1phosphorylation and desensitizes endothelial cells to thrombin signaling but promotes limited receptor cleavage and negligible internalization and degradation even after prolonged APC exposure. Thus, APC selective signaling and endothelial barrier protective effects are mediated through compartmentalization of PAR1in caveolae and a novel mechanism of PAR1signal regulation.
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DOI：
10.1176/ajp.154.4.562
发表时间：
1997-04
期刊：
The American journal of psychiatry
影响因子：
--
作者：
G. Alexopoulos;B. Meyers;R. Young;T. Kakuma;D. Silbersweig;M. Charlson
通讯作者：
G. Alexopoulos;B. Meyers;R. Young;T. Kakuma;D. Silbersweig;M. Charlson
老年心境恶劣患者停用氟西汀。
DOI：
--
发表时间：
1997
期刊：
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry
影响因子：
--
作者：
Devanand,DP;Kim,MK;Nobler,MS
通讯作者：
Nobler,MS
雌激素替代疗法对阿尔茨海默病患者他克林反应的影响
影响因子：
9.9
作者：
L. Schneider;M. Farlow;V. Henderson;J. Pogoda
通讯作者：
J. Pogoda
利培酮治疗痴呆患者的精神病和攻击行为
影响因子：
4.5
作者：
I. Katz;M. Brecher;C. Clyde;Judy Napolitano
通讯作者：
Judy Napolitano