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Proc Natl Acad Sci U S A
2005 Nov 15;10246:16777-82. doi: 10.1073/pnas.0508303102.
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WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis.
Rinehart J
,
Kahle KT
,
de Los Heros P
,
Vazquez N
,
Meade P
,
Wilson FH
,
Hebert SC
,
Gimenez I
,
Gamba G
,
Lifton RP
.
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WNK1 and WNK4 [WNK, with no lysine (K)] are serine-threonine kinases that function as molecular switches, eliciting coordinated effects on diverse ion transport pathways to maintain homeostasis during physiological perturbation. Gain-of-function mutations in either of these genes cause an inherited syndrome featuring hypertension and hyperkalemia due to increased renal NaCl reabsorption and decreased K(+) secretion. Here, we reveal unique biochemical and functional properties of WNK3, a related member of the WNK kinase family. Unlike WNK1 and WNK4, WNK3 is expressed throughout the nephron, predominantly at intercellular junctions. Because WNK4 is a potent inhibitor of members of the cation-cotransporter SLC12A family, we used coexpression studies in Xenopus oocytes to investigate the effect of WNK3 on NCC and NKCC2, related kidney-specific transporters that mediate apical NaCl reabsorption in the thick ascending limb and distal convoluted tubule, respectively. In contrast to WNK4's inhibitory activity, kinase-active WNK3 is a potent activator of both NKCC2 and NCC-mediated transport. Conversely, in its kinase-inactive state, WNK3 is a potent inhibitor of NKCC2 and NCC activity. WNK3 regulates the activity of these transporters by altering their expression at the plasma membrane. Wild-type WNK3 increases and kinase-inactive WNK3 decreases NKCC2 phosphorylation at Thr-184 and Thr-189, sites required for the vasopressin-mediated plasmalemmal translocation and activation of NKCC2 in vivo. The effects of WNK3 on these transporters and their coexpression in renal epithelia implicate WNK3 in NaCl, water, and blood pressure homeostasis, perhaps via signaling downstream of vasopressin.
Choate,
WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl- -transporting epithelia.
2003, Pubmed
Choate,
WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl- -transporting epithelia.
2003,
Pubmed
Ecelbarger,
Vasopressin-mediated regulation of epithelial sodium channel abundance in rat kidney.
2000,
Pubmed
Ecelbarger,
Regulation of the abundance of renal sodium transporters and channels by vasopressin.
2001,
Pubmed
Flemmer,
Activation of the Na-K-Cl cotransporter NKCC1 detected with a phospho-specific antibody.
2002,
Pubmed
Gamba,
Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters.
2005,
Pubmed
Giménez,
Short-term stimulation of the renal Na-K-Cl cotransporter (NKCC2) by vasopressin involves phosphorylation and membrane translocation of the protein.
2003,
Pubmed
Giménez,
Regulatory phosphorylation sites in the NH2 terminus of the renal Na-K-Cl cotransporter (NKCC2).
2005,
Pubmed
,
Xenbase
Golbang,
A new kindred with pseudohypoaldosteronism type II and a novel mutation (564D>H) in the acidic motif of the WNK4 gene.
2005,
Pubmed
,
Xenbase
Holden,
Cloning, genomic organization, alternative splicing and expression analysis of the human gene WNK3 (PRKWNK3).
2004,
Pubmed
Hoover,
N-Glycosylation at two sites critically alters thiazide binding and activity of the rat thiazide-sensitive Na(+):Cl(-) cotransporter.
2003,
Pubmed
,
Xenbase
Kahle,
WNK4 regulates apical and basolateral Cl- flux in extrarenal epithelia.
2004,
Pubmed
,
Xenbase
Kahle,
WNK3 modulates transport of Cl- in and out of cells: implications for control of cell volume and neuronal excitability.
2005,
Pubmed
,
Xenbase
Kahle,
WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion.
2003,
Pubmed
,
Xenbase
Kahle,
Paracellular Cl- permeability is regulated by WNK4 kinase: insight into normal physiology and hypertension.
2004,
Pubmed
Kahle,
Regulation of diverse ion transport pathways by WNK4 kinase: a novel molecular switch.
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,
Pubmed
Náray-Fejes-Tóth,
The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na+ transport.
2004,
Pubmed
Plata,
Functional properties of the apical Na+-K+-2Cl- cotransporter isoforms.
2002,
Pubmed
,
Xenbase
Simon,
Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.
1996,
Pubmed
Simon,
Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.
1996,
Pubmed
Veríssimo,
WNK kinases, a novel protein kinase subfamily in multi-cellular organisms.
2001,
Pubmed
Wilson,
Human hypertension caused by mutations in WNK kinases.
2001,
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
Xu,
WNK1 activates SGK1 to regulate the epithelial sodium channel.
2005,
Pubmed
Xu,
WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II.
2000,
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
