WNK1 and WNK4 modulate CFTR activity.
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.
Yang
Chao-Ling
CL
Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA. yangch@ohsu.edu
Liu
Xuehong
X
Paliege
Alex
A
Zhu
Xiaoman
X
Bachmann
Sebastian
S
Dawson
David C
DC
Ellison
David H
DH
D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006947:Hyperkalemia / Q000235:genetics; D006973:Hypertension / Q000235:genetics; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000076204:WNK Lysine-Deficient Protein Kinase 1; D014982:Xenopus laevis
C505032:CFTR protein, human; D015778:Minor Histocompatibility Antigens; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C499025:Wnk4 protein, rat; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498744:Wnk1 protein, mouse