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J Physiol
2006 Mar 01;571Pt 2:275-86. doi: 10.1113/jphysiol.2005.102202.
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WNK3, a kinase related to genes mutated in hereditary hypertension with hyperkalaemia, regulates the K+ channel ROMK1 (Kir1.1).
Leng Q, Kahle KT, Rinehart J, MacGregor GG, Wilson FH, Canessa CM, Lifton RP, Hebert SC.
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The serine-threonine kinase WNK3 modulates Cl- transport into and out of cells through its regulation of SLC12A cation/Cl- cotransporters, implicating it as (one of) the long-sought Cl-/volume-sensitive kinase(s). Integrators in homeostatic systems regulate structurally diverse but functionally coupled elements. For example, the related kinase WNK4 regulates the Na-Cl co-transporter (NCC), paracellular Cl- flux, and the K+ channel ROMK1 (Kir1.1) to maintain renal NaCl and K+ homeostasis; mutations in PRKWNK4, encoding WNK4, cause a Mendelian disease featuring hypertension and hyperkalemia. It is known that WNK3 is expressed in the nephron's distal convoluted tubule (DCT) and stimulates NCC activity. Here, we show that WNK3 is also expressed in cortical and outer medullary collecting duct principal cells. Accordingly, we tested WNK3's effect on the mediators of NaCl and K+ handling in these nephron segments--the epithelial sodium channel (ENaC), paracellular Cl- flux, and ROMK1--using established model systems. WNK3 did not alter paracellular Cl- flux in tetracycline-responsive MDCK II cells, nor affect amiloride-sensitive currents when co-expressed with ENaC in Xenopus laevis oocytes. However, additional co-expression studies in oocytes revealed WNK3 inhibited the renal-specific K+ channel ROMK1 activity greater than 5.5-fold (p < .0001) by altering its plasmalemmal surface expression; WNK3 did not affect ROMK1's conductance or open/closed probability. 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.
Choate,
WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl- -transporting epithelia.
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Choate,
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,
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Volume sensitivity of cation-Cl- cotransporters is modulated by the interaction of two kinases: Ste20-related proline-alanine-rich kinase and WNK4.
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,
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,
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,
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,
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,
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Paracellular Cl- permeability is regulated by WNK4 kinase: insight into normal physiology and hypertension.
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Molecular and cellular mechanisms of cardiac arrhythmias.
2001,
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Properties of WNK1 and implications for other family members.
2005,
Pubmed Lifton,
Molecular mechanisms of human hypertension.
2001,
Pubmed Min,
Crystal structure of the kinase domain of WNK1, a kinase that causes a hereditary form of hypertension.
2004,
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The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na+ transport.
2004,
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Phosphorylation-regulated endoplasmic reticulum retention signal in the renal outer-medullary K+ channel (ROMK).
2005,
Pubmed
,
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WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis.
2005,
Pubmed
,
Xenbase Shimkets,
The activity of the epithelial sodium channel is regulated by clathrin-mediated endocytosis.
1997,
Pubmed
,
Xenbase Valentijn,
Biosynthesis and processing of epithelial sodium channels in Xenopus oocytes.
1998,
Pubmed
,
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The molecular physiology of tight junction pores.
2004,
Pubmed Veríssimo,
WNK kinases, a novel protein kinase subfamily in multi-cellular organisms.
2001,
Pubmed Vitari,
The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases.
2005,
Pubmed Wilson,
Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.
2003,
Pubmed
,
Xenbase Wilson,
Human hypertension caused by mutations in WNK kinases.
2001,
Pubmed Xu,
WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II.
2000,
Pubmed Xu,
WNK1 activates SGK1 to regulate the epithelial sodium channel.
2005,
Pubmed Yamauchi,
Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins.
2004,
Pubmed
,
Xenbase Yang,
WNK kinases regulate thiazide-sensitive Na-Cl cotransport.
2003,
Pubmed
,
Xenbase Yang,
Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport.
2005,
Pubmed
