Journal article
Regulation of ROMK Channel and K+ Homeostasis by Kidney-specific WNK1 Kinase
The Journal of biological chemistry, Vol.284(18), pp.12198-12206
05/01/2009
DOI: 10.1074/jbc.M806551200
PMCID: PMC2673288
PMID: 19244242
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.
Details
- Title: Subtitle
- Regulation of ROMK Channel and K+ Homeostasis by Kidney-specific WNK1 Kinase
- Creators
- Zhen Liu - The University of Texas Southwestern Medical CenterHao-Ran Wang - The University of Texas Southwestern Medical CenterChou-Long Huang - The University of Texas Southwestern Medical Center
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.284(18), pp.12198-12206
- DOI
- 10.1074/jbc.M806551200
- PMID
- 19244242
- PMCID
- PMC2673288
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology
- Language
- English
- Date published
- 05/01/2009
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984359781102771
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