WNK1 and WNK4 modulate CFTR activity

Chao-Ling Yang, Xuehong Liu, Alex Paliege, Xiaoman Zhu, Sebastian Bachmann, David C. Dawson, David Ellison

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-gated chloride channel. WNK kinases are widely expressed modulators of ion transport. WNK1 and WNK4, two WNK kinases that are mutated in familial hyperkalemic hypertension (FHHt), are co-expressed with CFTR in several organs, raising the possibility that WNK kinases might alter CFTR activity in vivo or that CFTR could be involved in the pathogenesis of FHHt. Here, we report that WNK1 co-localizes with CFTR protein in pulmonary epithelial cells. Co-expression of WNK1 or WNK4 with CFTR in Xenopus laevis oocytes suppresses chloride channel activity. The effect of WNK4 is dose dependent and occurs, at least in part, by reducing CFTR protein abundance at the plasma membrane. This effect is independent of WNK4 kinase activity. In contrast, the effect of WNK1 on CFTR activity requires intact WNK1 kinase activity. Moreover WNK1 and WNK4 exhibit additive CFTR inhibition. Previous reports suggest that patients with FHHt exhibit mild changes in nasal potential difference that resemble the more severe changes that occur in cystic fibrosis. We report that the FHHt-causing mutant WNK4 Q562E is a more potent inhibitor of CFTR activity than is the wild-type WNK4. Taken together, these results suggest that WNK1 and WNK4 may modulate CFTR activity; they further suggest that WNK kinases may be potential therapeutic targets for cystic fibrosis.

Original languageEnglish (US)
Pages (from-to)535-540
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume353
Issue number3
DOIs
StatePublished - Feb 16 2007

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Phosphotransferases
Hypertension
Chloride Channels
Cystic Fibrosis
Ion Transport
Xenopus laevis
Cell membranes
Nose
Modulators
Oocytes
Proteins
Adenosine Triphosphate
Epithelial Cells
Cell Membrane
Ions

Keywords

  • Chloride channels
  • Cystic fibrosis
  • Familial hyperkalemic hypertension
  • Lung mutation
  • Na channels
  • Pseudohypoaldosteronism type II
  • WNK kinases

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

WNK1 and WNK4 modulate CFTR activity. / Yang, Chao-Ling; Liu, Xuehong; Paliege, Alex; Zhu, Xiaoman; Bachmann, Sebastian; Dawson, David C.; Ellison, David.

In: Biochemical and Biophysical Research Communications, Vol. 353, No. 3, 16.02.2007, p. 535-540.

Research output: Contribution to journalArticle

Yang, Chao-Ling ; Liu, Xuehong ; Paliege, Alex ; Zhu, Xiaoman ; Bachmann, Sebastian ; Dawson, David C. ; Ellison, David. / WNK1 and WNK4 modulate CFTR activity. In: Biochemical and Biophysical Research Communications. 2007 ; Vol. 353, No. 3. pp. 535-540.
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