Protease Nexin-1 and Thrombin: Injury-related Processes in the Brain
Protease Nexin-1 and Thrombin: Injury-related Processes in the Brain
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蛋白酶 Nexin-1 和凝血酶：大脑损伤相关过程
DOI：
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发表时间：
1993
影响因子：
6.7
通讯作者：
P. Vaughan
中科院分区：
文献类型：
--
作者：
Dennis Cunningham;L. Pulliam;P. Vaughan
凝血酶以其在血液凝固的最后阶段的作用而闻名，在那里它对血小板聚集和纤维蛋白形成的影响得到了很好的研究。此外，凝血酶还直接调节某些细胞的关键活性。例如，它对成纤维细胞和平滑肌细胞是有丝分裂的(1)，对单核细胞是切钙化的(2)。凝血酶对细胞的这些作用似乎参与了构成组织修复过程的一系列复杂事件。最近的研究表明，凝血酶还可以收缩培养的神经元和神经母细胞瘤细胞上的神经突（3,4），并将培养的星状星形胶质细胞转化为非固定的神经形态（5,6）。后一种效应包括星形胶质细胞变平和细胞上的突起收缩，这些突起在体内经常延伸到神经元或毛细血管。这些对神经元和星形胶质细胞的影响是凝血酶所特有的，因为许多其他蛋白酶的浓度更高，不会产生类似的影响。此外，它们还需要凝血酶的蛋白水解活性。显著。这些作用需要非常低浓度的凝血酶；对神经元和星形胶质细胞的半最大作用只需要小核浓度。一种类似于最近从血小板中克隆的凝血酶受体(7)似乎参与了这些反应，因为凝血酶受体激活肽可以产生与凝血酶对神经母细胞瘤细胞(8)和星形胶质细胞(9)相同的作用。凝血酶的上述作用可通过蛋白酶连接蛋白1 （PN-1）调节。PN-1是分泌43 kDa的丝氨酸蛋白酶抑制剂，溶液中可快速抑制凝血酶、尿激酶和纤溶酶（10）。PN-I通过与这些蛋白酶形成sds稳定的复合物来抑制这些蛋白酶；然后，pn - 1 -蛋白酶复合物与细胞结合，并迅速内化，并被分解（11）。这提供了一种在细胞外环境中抑制和清除蛋白酶的机制。游离PN-1与细胞外基质（ECM）紧密结合；这调节了它的活性和靶垂体特异性。PN-1与ECM结合可加速其对凝血酶的抑制，并阻断其抑制尿激酶和纤溶酶的能力（12）。因此，PN-I在细胞外环境中是一种特异性凝血酶抑制剂。事实上，通过抑制凝血酶，PN-1可以调节凝血酶的有丝分裂作用（33），促进神经元的神经突生长(3)，促进星形胶质细胞的星形形成(5)。Menard和cafIcagucs发现并研究了一种胶质源性神经突促进因子，即胶质源性连接蛋白（glia-derived nexin），它与PN-1相同（14,15）。
Thrombin is best known for its role in the final stages of blood coagulation where it has well studied effects on platelet aggregation and fibrin formation. In addition, thrombin directly regulates key activities of certain cells. For example, it is mitogenic for fibroblasts and smooth muscle cells (1) and chernotactic for monocytes (2). These effects of thrombin on cells appear to participate in the complex series of events that comprise the tissue repair process. Recent studies have shown that thrombin can also retract neurites on cultured neurons and neuroblastoma cells (3,4) and convert culturcd stellate astroglia to a nonstcIlate rnorphology (5,6). The latter effect involves a flattening of the astroglia and retraction of processes on the cells which in vivo frequently extend to neurons or capillaries. These effects on neurons and astroglia are specific for thrombin since much higher concentrations of a number of other proteases do not produce similar effects. Moreover, they require the proteolytic activity of thrombin. Significantly. these effects require very low concentrations of thrombin; half-maximal effects on both neurons and astroglia require only picornolar concentrations. A thrornhin receptor similar to the one recently cloned from platelets ( 7 ) appears to be involved in these responses, since effccts identical to thrombin on neuroblasloma cells (8) and astroglia (9) can be produced by thrombin receptor activating peptides. The above effects of thrombin can be regulared by prorease nexin-1 (PN-1). PN-1 is a secreted 43 kDa serine protease inhibitor which in solution rapidly inhibits thrombin, urokinase and plasmin (10). PN-I inhibits These proteases by forming SDS-stable complexes with them; the PN-l -protease complexes then bind to the cells and are rapidly internalized and d e ~ a d e d (1 1). This provides a mechanism for inhibiting and clearing proteases in the extracelIular environment. Free PN-1 binds tightly to the extracelluIar matrix (ECM); this regulates both its activity and target ptotease specificity. Binding of PN-1 Lo the ECM accelerates its inhibition of thrombin and blocks its ability to inhibit urokinase and plasmin (12). Thus, PN-I in the extracellular environment is a specific thrombin inhibitor. Indeed, by inhibiting thrombin, PN-1 can modulate the mitogenic effects of thrombin (33), promote neurite outgrowth from neurons (3) and promote stellation of astrocytes (5 ) . A glial-derived neurite promoting factor, glia-derived nexin, that was identified and studied by Menard and cafIcagucs, is identical to PN-1 (14,15).
DOI：
10.1016/s0021-9258(18)88883-4
发表时间：
1985-06
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Randy W. Scott;Barbara L. Bergman;Ani 1 Bajpai;R. Hersh;Henry Rodriguez;Barry N. Jonesd;Carlos Barredad;S. Watts;Joffre B. Bakera
通讯作者：
Randy W. Scott;Barbara L. Bergman;Ani 1 Bajpai;R. Hersh;Henry Rodriguez;Barry N. Jonesd;Carlos Barredad;S. Watts;Joffre B. Bakera