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Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10315-20. Epub 2005 Jul 8.

WNK1 activates SGK1 to regulate the epithelial sodium channel.

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1
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.

Abstract

WNK (with no lysine [K]) kinases are serine-threonine protein kinases with an atypical placement of the catalytic lysine. Intronic deletions increase the expression of WNK1 in humans and cause pseudohypoaldosteronism type II, a form of hypertension. WNKs have been linked to ion carriers, but the underlying regulatory mechanisms are unknown. Here, we report a mechanism for the control of ion permeability by WNK1. We show that WNK1 activates the serum- and glucocorticoid-inducible protein kinase SGK1, leading to activation of the epithelial sodium channel. Increased channel activity induced by WNK1 depends on SGK1 and the E3 ubiquitin ligase Nedd4-2. This finding provides compelling evidence that this molecular mechanism contributes to the pathogenesis of hypertension in pseudohypoaldosteronism type II caused by WNK1 and, possibly, in other forms of hypertension.

PMID:
16006511
PMCID:
PMC1177404
DOI:
10.1073/pnas.0504422102
[Indexed for MEDLINE]
Free PMC Article
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