Document Detail


WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4.
MedLine Citation:
PMID:  17018846     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The epithelial Ca(2+) channel TRPV5 serves as a gatekeeper for active Ca(2+) reabsorption in the distal convoluted tubule and connecting tubule of the kidney. WNK4, a protein serine/threonine kinase with gene mutations that cause familial hyperkalemic hypertension (FHH), including a subtype with hypercalciuria, is also localized in the distal tubule of the nephron. To understand the role of WNK4 in modulation of Ca(2+) reabsorption, we evaluated the effect of WNK4 on TRPV5-mediated Ca(2+) transport in Xenopus laevis oocytes. Coexpression of TRPV5 with WNK4 resulted in a twofold increase in TRPV5-mediated Ca(2+) uptake. The increase in Ca(2+) uptake was due to the increase in surface expression of TRPV5. When the thiazide-sensitive Na(+)-Cl(-) cotransporter NCC was coexpressed, the effect of WNK4 on TRPV5 was weakened by NCC in a dose-dependent manner. Although the WNK4 disease-causing mutants E562K, D564A, Q565E, and R1185C retained their ability to upregulate TRPV5, the blocking effect of NCC was further strengthened when wild-type WNK4 was replaced by the Q565E mutant, which causes FHH with hypercalciuria. We conclude that WNK4 positively regulates TRPV5-mediated Ca(2+) transport and that the inhibitory effect of NCC on this process may be involved in the pathogenesis of hypercalciuria of FHH caused by gene mutation in WNK4.
Authors:
Yi Jiang; William B Ferguson; Ji-Bin Peng
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-10-03
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  292     ISSN:  1931-857X     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-02-06     Completed Date:  2007-03-27     Revised Date:  2011-04-28    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F545-54     Citation Subset:  IM    
Affiliation:
Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, AL 35294-0006, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism*,  urine
Humans
Hypercalciuria / physiopathology
Hyperkalemia / genetics*
Hypertension / genetics*
Patch-Clamp Techniques
Protein-Serine-Threonine Kinases / genetics,  physiology*
TRPV Cation Channels / physiology*
Xenopus laevis
Chemical
Reg. No./Substance:
0/TRPV Cation Channels; 0/TRPV5 protein, human; 7440-70-2/Calcium; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/WNK4 protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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