The Na/K-ATPase-mediated signal transduction as a target for new drug development.
The Na/K-ATPase-mediated signal transduction as a target for new drug development.
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DOI：
10.2741/1766
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发表时间：
2005-09
期刊：
影响因子：
--
通讯作者：
Zijian Xie;Joe X. Xie
中科院分区：
文献类型：
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作者：
Zijian Xie;Joe X. Xie
Na/K-ATPase，或称Na+泵，是P型ATPase超家族的成员。除了泵送离子，Na/K-ATPase是一种受体，不仅调节蛋白激酶的功能，还充当支架，能够将不同的蛋白质捆绑成一个信号复合体。信号转导的Na/K-ATPase位于小窝中，与酪氨酸激酶Src形成“二元受体”。内源性强心类固醇和洋地黄类药物如哇巴因作为激动剂，刺激这种二元受体，导致与信号Na/K-ATPase相关或接近的蛋白质的酪氨酸磷酸化。随后，这启动了包括ERKs和PKC同工酶在内的蛋白激酶级联反应。它还增加线粒体产生的活性氧物种(ROS)，并调节细胞内钙离子浓度。与其他受体一样，哇巴因激活Na/K-ATPase/Src可诱导质膜Na/K-ATPase内吞。值得注意的是，这种新近认识到的Na/K-ATPase的信号功能似乎在许多心血管疾病的发病机制中发挥着重要作用，因此成为开发新的治疗药物的重要靶点。
The Na/K-ATPase, or Na+ pump, is a member of the P-type ATPase superfamily. In addition to pumping ions, the Na/K-ATPase is a receptor that not only regulates the function of protein kinases, but also acts as a scaffold, capable of tethering different proteins into a signalplex. The signaling Na/K-ATPase resides in caveolae and forms a "binary receptor" with the tyrosine kinase Src. Endogenous cardiotonic steroids and digitalis drugs such as ouabain act as agonists and provoke this binary receptor, resulting in tyrosine phosphorylation of the proteins that are either associated with, or in close proximity to, the signaling Na/K-ATPase. Subsequently, this initiates protein kinase cascades including ERKs and PKC isozymes. It also increases mitochondrial production of reactive oxygen species (ROS) and regulates intracellular calcium concentration. Like other receptors, activation of the Na/K-ATPase/Src by ouabain induces the endocytosis of the plasma membrane Na/K-ATPase. Significantly, this newly appreciated signaling function of the Na/K-ATPase appears to play an important role in the pathogenesis of many cardiovascular diseases, therefore serving as an important target for development of novel therapeutic agents.