Regulation of sodium pump endocytosis by cardiotonic steroids: Molecular mechanisms and physiological implications.
Regulation of sodium pump endocytosis by cardiotonic steroids: Molecular mechanisms and physiological implications.
复制标题
DOI：
10.1016/j.pathophys.2007.09.008
复制
发表时间：
2007-12-01
期刊：
影响因子：
--
通讯作者：
Shapiro, Joseph I
中科院分区：
文献类型：
--
作者：
Liu, Jiang;Shapiro, Joseph I
我们先前已经证明哇巴因和其他强心类固醇与血浆Na/K-ATPase相互作用，并导致Na/K-ATPase的内吞作用具有时间和剂量依赖性。这种内吞作用可以用荧光成像以及常规的生化和生物物理细胞分离方法来证明。在近端小管细胞中，这一过程似乎直接调节了基底侧Na/K-ATPase的表达密度，也间接调节了跨上皮钠的运输。基因操作以及药物和细胞培养模型的研究表明，强心类固醇刺激的血浆Na/K-ATPase内吞需要小窝蛋白和笼状蛋白，以及c-Src的激活，EGFR的反式激活和PI3K的激活。有趣的是，c-Src、EGFR和ERK1/2似乎都与质膜Na/K-ATPase一起被内吞。这些观察结果表明，质膜Na/K-ATPase的一个子集与传统受体酪氨酸激酶的信号伴侣之间存在密切的相似之处。虽然这种内吞作用在Na/K-ATPase信号级联中的作用以及信号转导的极限还需要进一步的研究，但我们认为它在调节肾脏钠处理以及其他重要过程中具有重要作用。
We have previously shown that ouabain and other cardiotonic steroids interact with the plasmalemmal Na/K-ATPase and cause a time and dose dependent endocytosis of the Na/K-ATPase. This endocytosis is demonstrable using fluorescence imaging as well as conventional biochemical and biophysical cell separation methods. In proximal tubule cells, this process appears to regulate the density of basolateral Na/K-ATPase expression directly as well as indirectly modulate transepithelial sodium transport. Work with genetic manipulations, as well as pharmacological agents with cell culture models, have demonstrated that the cardiotonic steroid stimulated endocytosis of the plasmalemmal Na/K-ATPase requires caveolin and clathrin as well as the activation of c-Src, transactivation of the EGFR and activation of PI3K. Interestingly c-Src, EGFR and ERK1/2 all appear to be endocytosed along with the plasmalemmal Na/K-ATPase. These observations suggest a close analogy between a subset of plasmalemmal Na/K-ATPase and signaling companions with conventional receptor tyrosine kinases. While further studies are necessary to delineate the role of this endocytosis in the generation as well as the limit of signal transduction through the Na/K-ATPase signal cascade, we propose that it has an important role in the regulation of renal sodium handling as well as other important processes.