Regulation of ROMK channel and K+ homeostasis by kidney-specific WNK1 kinase

Zhen Liu, Hao Ran Wang, Chou Long Huang

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

WNK kinases are serine-threonine kinases with an atypical placement of the catalytic lysine. WNK1, the first member discovered, has multiple alternatively spliced isoforms, including a ubiquitously expressed full-length long form (L-WNK1) and a kidney-specific form (KS-WNK1) predominantly expressed in the kidney. Intronic deletions of WNK1 that increase WNK1 transcript cause pseudohypoaldosteronism type 2, an autosomal-dominant disease characterized by hypertension and hyperkalemia. L-WNK1 inhibits renal K+ channel ROMK, likely contributing to hyperkalemia in PHAII. Previously, we reported that KS-WNK1 by itself has no effect on ROMK1 but antagonizes L-WNK1-mediated inhibition of ROMK1. Amino acids 1-253 of KS-WNK1 (KS-WNK1(1-253)) are sufficient for reversing the inhibition of ROMK1 caused by L-WNK1(1-491). Here, we further investigated the mechanisms by which KS-WNK1 counteracts L-WNK1 regulation of ROMK1. We reported that two regions of KS-WNK1(1-253) are involved in the antagonism of L-WNK1; one includes the first 30 amino acids unique for KS-WNK1 encoded by the alternatively spliced initiating exon 4A, and the other is equivalent to the autoinhibitory domain (AID) of L-WNK1. Mutations of two phenylalanine residues known to be critical for autoinhibitory function of AID abolish the ability of the AID region of KS-WNK1 to antagonize L-WNK1. To examine the physiological role of KS-WNK1 in the regulation of renal K+ secretion, we generated transgenic mice that overexpress amino acids 1-253 of KS-WNK1 under the control of a kidney-specific promoter. Transgenic mice have lower serum K+ levels and higher urinary fractional excretion of K+ compared with wild type littermates despite the same amount of daily urinary K+ excretion. Moreover, transgenic mice (compared with wild type littermates) displayed a higher abundance of ROMK on the apical membrane of distal nephron. Thus, KS-WNK1 is an important physiological regulator of renal K+ excretion, likely through its effects on the ROMK1 channel.

Original languageEnglish (US)
Pages (from-to)12198-12206
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number18
DOIs
StatePublished - May 1 2009

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Homeostasis
Phosphotransferases
Kidney
Amino Acids
Transgenic Mice
Hyperkalemia
Protein-Serine-Threonine Kinases
Phenylalanine
Pseudohypoaldosteronism
Lysine
Exons
Protein Isoforms
L Forms
Membranes
Nephrons
Hypertension
Mutation
Serum

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Regulation of ROMK channel and K+ homeostasis by kidney-specific WNK1 kinase. / Liu, Zhen; Wang, Hao Ran; Huang, Chou Long.

In: Journal of Biological Chemistry, Vol. 284, No. 18, 01.05.2009, p. 12198-12206.

Research output: Contribution to journalArticle

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