Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Am J Physiol Renal Physiol
2008 Oct 01;2954:F1199-206. doi: 10.1152/ajprenal.90396.2008.
Show Gene links
Show Anatomy links
WNK3 and WNK4 amino-terminal domain defines their effect on the renal Na+-Cl- cotransporter.
San-Cristobal P, Ponce-Coria J, Vázquez N, Bobadilla NA, Gamba G.
???displayArticle.abstract???
Loss of physiological regulation of the renal thiazide-sensitive Na+-Cl- cotransporter (NCC) by mutant WNK1 or WNK4 results in pseudohypoaldosteronism type II (PHAII) characterized by arterial hypertension and hyperkalemia. WNK4 normally inhibits NCC, but this effect is lost by eliminating WNK4 catalytic activity or through PHAII-type mutations. In contrast, another member of the WNK family, WNK3, activates NCC. The positive effect of WNK3 on NCC also requires its catalytic activity. Because the opposite effects of WNK3 and WNK4 on NCC were observed in the same expression system, sequences within the WNKs should endow these kinases with their activating or inhibiting properties. To gain insight into the structure-function relationships between the WNKs and NCC, we used a chimera approach between WNK3 and WNK4 to elucidate the domain of the WNKs responsible for the effects on NCC. Chimeras were constructed by swapping the amino or carboxyl terminus domains, which flank the central kinase domain, between WNK3 and WNK4. Our results show that the effect of chimeras toward NCC follows the amino-terminal domain. Thus the amino terminus of the WNKs contains the sequences that are required for their activating or inhibiting properties on NCC.
Adragna,
Regulation of K-Cl cotransport: from function to genes.
2004, Pubmed
Adragna,
Regulation of K-Cl cotransport: from function to genes.
2004,
Pubmed Cai,
WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells.
2006,
Pubmed
,
Xenbase Delaloy,
Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform.
2003,
Pubmed de Los Heros,
WNK3 bypasses the tonicity requirement for K-Cl cotransporter activation via a phosphatase-dependent pathway.
2006,
Pubmed
,
Xenbase Flatman,
Regulation of Na-K-2Cl cotransport by phosphorylation and protein-protein interactions.
2002,
Pubmed Flatman,
Cotransporters, WNKs and hypertension: important leads from the study of monogenetic disorders of blood pressure regulation.
2007,
Pubmed Gagnon,
Volume sensitivity of cation-Cl- cotransporters is modulated by the interaction of two kinases: Ste20-related proline-alanine-rich kinase and WNK4.
2006,
Pubmed
,
Xenbase Gamba,
Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters.
2005,
Pubmed Gamba,
Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney.
1994,
Pubmed
,
Xenbase Garzón-Muvdi,
WNK4 kinase is a negative regulator of K+-Cl- cotransporters.
2007,
Pubmed
,
Xenbase Golbang,
Regulation of the expression of the Na/Cl cotransporter by WNK4 and WNK1: evidence that accelerated dynamin-dependent endocytosis is not involved.
2006,
Pubmed
,
Xenbase Hebert,
Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family.
2004,
Pubmed Kahle,
WNK protein kinases modulate cellular Cl- flux by altering the phosphorylation state of the Na-K-Cl and K-Cl cotransporters.
2006,
Pubmed Kahle,
WNK3 modulates transport of Cl- in and out of cells: implications for control of cell volume and neuronal excitability.
2005,
Pubmed
,
Xenbase Lalioti,
Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule.
2006,
Pubmed Lauf,
K-Cl cotransport: properties and molecular mechanism.
2000,
Pubmed
,
Xenbase Lenertz,
Properties of WNK1 and implications for other family members.
2005,
Pubmed Mayan,
Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density.
2002,
Pubmed McCormick,
WNK kinases and renal sodium transport in health and disease: an integrated view.
2008,
Pubmed Moreno,
Affinity-defining domains in the Na-Cl cotransporter: a different location for Cl- and thiazide binding.
2006,
Pubmed
,
Xenbase Moriguchi,
WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1.
2005,
Pubmed O'Reilly,
WNK1, a gene within a novel blood pressure control pathway, tissue-specifically generates radically different isoforms with and without a kinase domain.
2003,
Pubmed O'Reilly,
Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo.
2006,
Pubmed
,
Xenbase Pacheco-Alvarez,
The Na+:Cl- cotransporter is activated and phosphorylated at the amino-terminal domain upon intracellular chloride depletion.
2006,
Pubmed
,
Xenbase Peng,
WNK4-mediated regulation of renal ion transport proteins.
2007,
Pubmed
,
Xenbase Ponce-Coria,
Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases.
2008,
Pubmed
,
Xenbase Rinehart,
WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis.
2005,
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 Song,
Molecular, functional, and genomic characterization of human KCC2, the neuronal K-Cl cotransporter.
2002,
Pubmed
,
Xenbase Subramanya,
Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform.
2006,
Pubmed
,
Xenbase 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 Wang,
Domains of WNK1 kinase in the regulation of ROMK1.
2008,
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,
Regulation of WNK1 by an autoinhibitory domain and autophosphorylation.
2002,
Pubmed Xu,
WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II.
2000,
Pubmed Yang,
The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex.
2007,
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 Yang,
Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model.
2007,
Pubmed
