Kinases as targets for ENaC regulation.
Kinases as targets for ENaC regulation.
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DOI：
10.2174/18744672112059990028
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发表时间：
2013-02
影响因子：
2.7
通讯作者：
D. Baines
中科院分区：
文献类型：
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作者：
D. Baines
阿米洛利敏感性上皮钠通道（ENaCs）转运Na+，并且对于跨上皮组织的盐和流体稳态是必需的。肾和肺组织的几种病理状况与ENaC功能异常相关。调节ENaC活性的信号通路利用许多激酶。近年来，人们发现了更多的病毒，并且它们的作用机制也得到了扩展。SGK和PKA的功能是最好理解的，并且都上调ENaC活性。SGK是PI 3 K通过PDK 1和TORC 2的重要靶点，而PKA与具有互补作用的其他激酶的活性相关。CK 2、GRK 2、IKKβ和PKD 1也上调ENaC。相反，PKC、ERK 1/2和AMPK是抑制性的。激酶作用的两个关键趋同目标仍然存在。这些是Nedd 4 -2和ENaC的β和γ亚基的磷酸化。取决于靶向的位点，磷酸化主要促进或减少这些蛋白质之间的缔合，以调节ENaC的回收及其随后在膜中的丰度。替代的新兴靶点包括参与ENaC通道向膜的易位和再循环的蛋白质。靶向激酶以在体内修饰ENaC功能已经显示出一些前景。SGK的失活对肾功能产生了轻微但积极的影响。激活PKA已显示出在肺部病理学中的潜力。PI 3 K和PKB的抑制可证明在肾Na+处理中的糖尿病相关改变中有用，AMPK的激活也是如此，这也可能在与ENaC活性升高相关的肺部病理学的治疗中具有潜力。
Amiloride-sensitive epithelial sodium channels (ENaCs) transport Na+ and are essential for salt and fluid homeostasis across epithelial tissues. Several pathological conditions of renal and pulmonary tissues are associated with abnormal ENaC function. The signalling pathways that regulate ENaC activity utilise a number of kinases. Over recent years, more have been identified and their mechanisms of action expanded. The functions of SGK and PKA are the best understood and both up-regulate ENaC activity. SGK is an important target of PI3K via PDK1 and TORC2 whilst PKA is linked with the activity of other kinases that have complementary effects. CK2, GRK2, IKKβ and PKD1 also up-regulate ENaC. In contrast, PKC, ERK1/2 and AMPK are inhibitory. Two key convergence targets for kinase action persist. These are phosphorylation of Nedd4-2 and the β and γ subunits of ENaC. Depending on the sites targeted, phosphorylation predominantly promotes or decreases association between these proteins to regulate ENaC retrieval and its subsequent abundance in the membrane. Alternative emerging targets include proteins involved in the translocation and recycling of ENaC channels to the membrane. Targeting kinases to modify ENaC function in vivo has shown some promise. Inactivation of SGK has produced mild but positive effects on renal function. Activating PKA has shown potential in lung pathologies. Inhibition of PI3K and PKB may prove useful in diabetic related alterations in renal Na+ handling, as could activation of AMPK, which may also have potential in the treatment of pulmonary pathologies associated with elevated ENaC activity.