WNK4 inhibits Ca(2+)-activated big-conductance potassium channels (BK) via mitogen-activated protein kinase-dependent pathway.
WNK4 inhibits Ca(2+)-activated big-conductance potassium channels (BK) via mitogen-activated protein kinase-dependent pathway.
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DOI：
10.1016/j.bbamcr.2013.05.004
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发表时间：
2013-10
影响因子：
5.1
通讯作者：
Wang, Wen-Hui
中科院分区：
文献类型：
--
作者：
Yue, Peng;Zhang, Chengbiao;Lin, Dao-Hong;Sun, Peng;Wang, Wen-Hui
采用穿孔全细胞记录技术研究了无赖氨酸激酶4（With-No-Lysine Kinase 4，WNK 4）对转染BK-α亚基（BK-α）的HEK 293 T细胞钙激活大电导钾通道（BK）的影响。WNK 4的表达抑制BK通道，降低外向钾电流。SGK 1的共表达可消除WNK 4对BK通道的抑制作用，恢复外向钾电流。WNK 4S 1169 D//1196 D的表达，其中两个SGK 1磷酸化位点（丝氨酸1169和1196）突变为天冬氨酸，对BK通道没有影响。此外，在BKα + WNK 4 S1169 D//1196 D转染的细胞中，SGK 1的共表达对K电流没有额外的影响，表明SGK 1通过刺激WNK 4磷酸化来逆转WNK 4诱导的BK通道抑制。WNK 4的表达而非WNK 4 S1169 D//1196 D的表达增加了ERK和p38丝裂原活化蛋白激酶（MAPK）的磷酸化; SGK 1的共表达消除了这种作用。抑制ERK和P38 MAPK可完全消除WNK 4对BK通道的抑制作用，这进一步表明ERK和P38 MAPK在介导WNK 4对BK通道的作用中的作用。与此相反，MAPK的抑制不能消除WNK 4对ROMK通道在HEK细胞和爪蟾卵母细胞的抑制作用。表达显性负性动力蛋白K44 A（DynK 44 A）或用动力蛋白抑制剂dynasore处理细胞，不仅增加K电流，而且在很大程度上消除了WNK 4对BK通道的抑制作用。然而，抑制MAPK仍然增加了BKα+ WNK 4转染并经Dynasore处理的细胞的外向K电流。在天然组织中进行的实验中获得了类似的结果，其中ERK和p38 MAPK的抑制增加了用dynasore处理的皮质集合管（CCD）中的BK通道活性。我们的结论是，WNK 4通过刺激ERK和p38 MAPK抑制BK通道，WNK 4激活MAPK可能通过刺激内吞作用以外的机制部分抑制BK通道。
We used the perforated whole-cell recording technique to examine the effect of With-No-Lysine Kinase 4 (WNK4) on the Ca2+ activated big-conductance K channels (BK) in HEK293T cells transfected with BK–α subunit (BK-α). Expression of WNK4 inhibited BK channels and decreased the outward K currents. Coexpression of SGK1 abolished the inhibitory effect of WNK4 on BK channels and restored the outward K currents. Expression of WNK4S1169D//1196D, in which both SGK1-phosphorylation sites (serine 1169 and 1196) were mutated to aspartate, had no effect on BK channels. Moreover, coexpression of SGK1 had no additional effect on K currents in the cells transfected with BKα + WNK4 S1169D//1196D, suggesting that SGK1 reversed WNK4-induced inhibition of BK channels by stimulating WNK4 phosphorylation. Expression of WNK4 but not WNK4 S1169D//1196D increased the phosphorylation of ERK and p38 mitogen-activated protein kinase (MAPK); an effect was abolished by coexpression of SGK1. The role of ERK and p38 MAPK in mediating the effect of WNK4 on BK channels was further suggested by the finding that inhibition of ERK and P38 MAPK completely abolished the inhibitory effect of WNK4 on BK channels. In contrast, inhibition of MAPK failed to abolish the inhibitory effect of WNK4 on ROMK channels in both HEK cells and Xenopus oocytes. Expression of dominant negative dynaminK44A (DynK44A) or treatment of the cells with dynasore, a dynamin inhibitor, not only increased K currents but also largely abolished the inhibitory effect of WNK4 on BK channels. However, inhibition of MAPK still increased the outward K currents in the cells transfected with BKα+WNK4 and treated with dynasore. Similar results were obtained in experiments performed in the native tissue in which inhibition of ERK and p38 MAPK increased BK channel activity in the cortical collecting duct (CCD) treated with dynasore. We concluded that WNK4 inhibited BK channels by stimulating ERK and p38 MAPK and that activation of MAPK by WNK4 may inhibit BK channels partially via a mechanism other than stimulating endocytosis.
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影响因子：
30.8
作者：
Lalioti, Maria D.;Zhang, Junhui;Lifton, Richard P.
通讯作者：
Lifton, Richard P.
DOI：
10.1152/ajprenal.00018.2007
发表时间：
2007-07-01
影响因子：
4.2
作者：
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作者：
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DOI：
10.1152/ajprenal.00169.2004
发表时间：
2004-11-01
影响因子：
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作者：
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Palmer, LG
影响因子：
4.8
作者：
ALESSI, DR;CUENDA, A;SALTIEL, AR
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