WNK3,相关激酶基因突变与高钾血症遗传性高血压,调节K +通道ROMK1 (Kir1.1)。
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愣了问,卡利KT,莱因哈特J,麦格雷戈GG,威尔逊FH Canessa厘米,Lifton RP,赫伯特SC
WNK3,相关激酶基因突变与高钾血症遗传性高血压,调节K +通道ROMK1 (Kir1.1)。
杂志。2006年3月1;571 (Pt 2): 275 - 86。Epub 2005年12月15日。
- PubMed ID
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16357011 (在PubMed]
- 文摘
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serine-threonine激酶WNK3调节Cl -运输的细胞通过其监管SLC12A阳离子/ Cl -转运蛋白,暗示这是(之一)长期Cl - / volume-sensitive激酶(年代)。在稳态系统集成商调节结构不同但功能耦合的元素。例如,相关激酶WNK4调节Na-Cl co-transporter (NCC) paracellular Cl -通量和K +通道ROMK1 (Kir1.1)维持肾脏生理盐水和K +体内平衡;突变PRKWNK4,编码WNK4,造成孟德尔疾病包括高血压和血钾过高。众所周知,WNK3表达在肾元远曲小管(DCT)和刺激NCC的活动。在这里,我们表明,WNK3也表示在皮层和髓集合管外的主要细胞。因此,我们测试了WNK3对介质的影响的生理盐水和K +处理这些肾元段——上皮钠通道(钠),paracellular Cl -通量,ROMK1,利用建立的模型系统。WNK3没有改变paracellular Cl -通量tetracycline-responsive II MDCK细胞,也不影响amiloride-sensitive电流中的钠时在非洲爪蟾蜍光滑的卵母细胞。然而,额外co-expression研究卵母细胞显示WNK3抑制renal-specific K +通道ROMK1活动大于5.5倍(p <。)通过改变其plasmalemmal表面表达;WNK3并不影响ROMK1电导或打开/关闭概率。 In contrast, WNK3 had no effect on the activity of the cardiac long-QT syndrome K+ channel KCNQ1/KCNE1 when co-expressed in oocytes. Inhibition of ROMK1 is independent of WNK3's catalytic activity and is mediated by WNK3's carboxyl terminus--a mechanism distinct from its known kinase-dependent activation of NCC. A kinase-inactivating point mutation, or a missense mutation homologous to one in WNK4 that causes disease produced a gain-of-function effect, enhancing WNK3's inhibition of ROMK1 greater than 2.5-fold relative to wild type kinase (p < .0001). The magnitude and specificity of WNK3's effects at both NCC and ROMK1, its co-expression with its targets in the distal nephron, and the established in vivo effect of WNK4 at these same targets provide evidence that WNK3's action is physiologically relevant. WNK3 is likely a component of one of the mechanisms that determines the balance between renal NaCl reabsorption and K+ secretion.