Receptor tyrosine kinases mediate epithelial Na(+) channel inhibition by epidermal growth factor.
Receptor tyrosine kinases mediate epithelial Na(+) channel inhibition by epidermal growth factor.
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DOI：
10.1152/ajprenal.00261.2004
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
Q. Tong;J. Stockand
中科院分区：
文献类型：
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作者：
Q. Tong;J. Stockand
表皮生长因子（EGF）可减少远端肾单位上皮对Na+的重吸收。上皮Na（+）通道（ENaC）的活性限制了肾单位这一部分的Na（+）转运。异常的ENaC活性和EGF信号都与位于远端肾单位的多囊肾疾病相关。我们在这里测试了EGF和受体酪氨酸激酶（RTK）的其他配体是否降低ENaC活性。EGF能迅速降低ENaC活性。RTK抑制剂erbstatin阻断EGF对ENaC的作用，当单独加入时增加通道活性，揭示内源性RTK的基础抑制。蛋白酪氨酸磷酸酶抑制剂钒酸盐，类似于EGF，降低ENaC活性。生长因子和钒酸盐通过降低开放概率降低ENaC活性。ENaC在EGF的作用下没有被磷酸化，这表明中间蛋白将EGF受体（EGFR）的抑制信号传递给ENaC。我们发现MAPK 1/2和c-Src都不是EGFR和ENaC之间的信号中介。抑制ENaC可降低质膜磷脂酰肌醇4，5-二磷酸水平[PtdIns（4，5）P（2）]，并可通过阻断PtdIns（4，5）P（2）消除。我们的结论是，EGF和RTK的其他配体通过降低膜PtdIns（4，5）P（2）水平来降低ENaC开放概率。
Epidermal growth factor (EGF) decreases Na(+) reabsorption across distal nephron epithelia. Activity of the epithelial Na(+) channel (ENaC) is limiting for Na(+) transport in this portion of the nephron. Abnormal ENaC activity and EGF signaling are both associated with polycystic kidney disease localized to the distal nephron. We tested here whether EGF and other ligands for receptor tyrosine kinases (RTK) decrease ENaC activity. EGF markedly and quickly decreased ENaC activity. The RTK inhibitor erbstatin blocked EGF actions on ENaC and when added alone increased channel activity, uncovering basal suppression by endogenous RTK. The protein tyrosine phosphatase inhibitor vanadate, similar to EGF, decreased ENaC activity. Growth factors and vanadate decreased ENaC activity by decreasing open probability. ENaC was not phosphorylated in response to EGF, indicating that intermediary proteins transduce the inhibitory signal from the EGF receptor (EGFR) to ENaC. We find that neither MAPK 1/2 nor c-Src is signaling intermediaries between EGFR and ENaC. Inhibition of ENaC paralleled decreases in plasma membrane phosphatidylinositol 4,5-bisphosphate levels [PtdIns(4,5)P(2)] and was abolished by clamping PtdIns(4,5)P(2). We conclude that EGF and other ligands for RTK decrease ENaC open probability by decreasing membrane PtdIns(4,5)P(2) levels.