The serum and glucocorticoid-inducible kinase SGK1 and the Na+/H+ exchange regulating factor NHERF2 synergize to stimulate the renal outer medullary K+ channel ROMK1
The serum and glucocorticoid-inducible kinase SGK1 and the Na+/H+ exchange regulating factor NHERF2 synergize to stimulate the renal outer medullary K+ channel ROMK1
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DOI：
10.1097/01.asn.0000035085.54451.81
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发表时间：
2002-12-01
影响因子：
13.6
通讯作者：
Lang, F
中科院分区：
文献类型：
--
作者：
Yun, CC;Palmada, M;Lang, F
盐皮质激素刺激连接小管和集合管主细胞的Na+重吸收和K+分泌：参与的离子通道分别为ENaC和ROMK 1。在非洲爪蟾卵母细胞中，血清和糖皮质激素敏感性激酶SGK1已被证明通过增加其在质膜中的丰度来增加ENaC活性。用同样的方法，ROMK 1似乎对SGK 1的调节不敏感。另一方面，ROMK1已显示与NHERF2共定位，NHERF2是一种介导转运蛋白靶向和转运到细胞膜中的蛋白质。本研究旨在检测SGK1对ROMK1的调节是否需要NHERF2。NHERF2和SGK1与ROMK1的共表达均不增加ROMK1活性。然而，NHERF 2和SGK 1与ROMK 1一起共表达显著增加K+通道活性。SGK1和NHERF2的组合作用不显著改变通道的IN关系，但增加了膜中通道的丰度，并降低了用布雷菲德菌素抑制囊泡插入后通道活性的衰减。NHERF2和SGK1的共表达不改变胞质pH，但导致ROMK1的pK（a）向更酸性的值轻微偏移。总之，NHERF2和SGK1相互作用，在很大程度上通过增强细胞膜内通道蛋白的丰度来增强ROMK1活性。这种相互作用使得SGK1和NHERF2的基因组调控和激活整合在ROMK1活性和肾K+排泄的控制中。
Mineralocorticoids stimulate Na+ reabsorption and K+ secretion in principal cells of connecting tubule and collecting duct: The involved ion channels are ENaC and ROMK1, respectively. In Xenopus oocytes, the serum and glucocorticoid-sensitive kinase SGK1 has been shown to increase ENaC activity by enhancing its abundance in the plasma membrane. With the same method, ROMK1 appeared to be insensitive to regulation by SGK1. On the other hand, ROMK1 has been shown to colocalize with NHERF2, a protein mediating targeting and trafficking of transport proteins into the cell membrane. The present study has been performed to test whether NHERF2 is required for regulation of ROMK1 by SGK1. Coexpression of neither NHERF2 nor SGK1 with ROMK1 increases ROMK1 activity. However, coexpression of NHERF2 and SGK1 together with ROMK1 markedly increases K+ channel activity. The combined effect of SGK1 and NHERF2 does not significantly alter the IN relation of the channel but increases the abundance of the channel in the membrane and decreases the decay of channel activity after inhibition of vesicle insertion with brefeldin. Coexpression of NHERF2 and SGK1 does not modify cytosolic pH but leads to a slight shift of pK(a) of ROMK1 to more acidic values. In conclusion, NHERF2 and SGK1 interact to enhance ROMK1 activity in large part by enhancing the abundance of channel protein within the cell membrane. This interaction allows the integration of genomic regulation and activation of SGK1 and NHERF2 in the control of ROMK1 activity and renal K+ excretion.