WNK1 kinase isoform switch regulates renal potassium excretion

Proc Natl Acad Sci U S A. 2006 May 30;103(22):8558-63. doi: 10.1073/pnas.0603109103. Epub 2006 May 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Electrophysiology
  • Gene Expression Regulation
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Kidney / drug effects
  • Kidney / metabolism*
  • Male
  • Oocytes / metabolism
  • Patch-Clamp Techniques
  • Potassium / metabolism*
  • Potassium / pharmacology
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Xenopus laevis


  • Isoenzymes
  • Potassium Channels, Inwardly Rectifying
  • Protein Serine-Threonine Kinases
  • Potassium