WNK1 kinase isoform switch regulates renal potassium excretion

James B. Wade, Liang Fang, Jie Liu, Dimin Li, Chao Ling Yang, Arohan R. Subramanya, Djikolngar Maouyo, Amanda Mason, David H. Ellison, Paul A. Welling

Research output: Contribution to journalArticlepeer-review

105 Scopus citations


Members of the WNK family of serine threonine kinases have been implicated as important modulators of salt homeostasis, regulating the balance between renal sodium reabsorption and potassium excretion. Gain-of-expression mutations in the WNK1 gene uncouple Na+ and K+ balance and cause a familial disorder of diminished renal potassium excretion, excessive sodium retention, and hypertension (pseudohypoaldosteronism type II or Gordon's syndrome). Alternative splicing of the WNK1 gene produces a kidney-specific short form of WNK1 (KS-WNK1) and a more ubiquitous long form (L-WNK1), but it is not clear how either of these isoforms influence renal potassium excretion. Here we demonstrate that KS-WNK1 and L-WNK1 converge in a pathway to regulate the renal outer-medullary K+ channel, Kir1.1. Reconstitution studies in Xenopus oocytes reveal that L-WNK1 significantly inhibits Kir1.1 by reducing cell surface localization of the channel. A catalytically inactive L-WNK1 mutant has no inhibitory effect on Kir1.1, indicating that channel inhibition depends on kinase activity. KS-WNK1, lacking an intact kinase domain, does not directly alter Kir1.1. Instead, KS-WNK1 negatively regulates L-WNK1 to release Kir1.1 from inhibition. Acute dietary potassium loading increases the relative abundance of KS-WNK1 to L-WNK1 transcript and protein in the kidney, indicating that physiologic up-regulation of Kir1.1 activity involves a WNK1 isoform switch and KS-WNK1-mediated release from L-WNK1 inhibition. Thus, these observations provide evidence for the physiological regulation of Na+ and K + balance by a kinase isoform switch mechanism.

Original languageEnglish (US)
Pages (from-to)8558-8563
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number22
StatePublished - May 30 2006
Externally publishedYes


  • Gordon's syndrome
  • Hypertension
  • Kir1.1 renal outer-medullary K channel
  • WNK kinase

ASJC Scopus subject areas

  • General


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