Antagonistic Regulation of ROMK by Long and Kidney-Specific WNK1 Isoforms

WNK kinases are serine-threonine kinases with an atypical placement of the catalytic lysine. Intronic deletions with increased expression of a ubiquitous long WNK1 transcript cause pseudohypoaldosteronism type 2 (PHA II), characterized by hypertension and hyperkalemia. Here, we report that long WNK1...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-01, Vol.103 (5), p.1615-1620
Main Authors: Lazrak, Ahmed, Liu, Zhen, Huang, Chou-Long
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino acids
Animals
Antagonist drugs
B lymphocytes
Biological Sciences
Blotting, Western
Cell Line
Clathrin - metabolism
Diet
DNA - chemistry
DNA - metabolism
Dose-Response Relationship, Drug
Dynamins - metabolism
Electrophysiology
Endocytosis
Enzymes
Exons
Female
Gene expression
Gene Expression Regulation
Genetic mutation
Green Fluorescent Proteins - metabolism
Humans
Hyperkalemia
Hypertension
Immunoprecipitation
Intracellular Signaling Peptides and Proteins
Kidney - metabolism
Kidneys
Male
Minor Histocompatibility Antigens
Models, Biological
Models, Genetic
Molecular Sequence Data
Mutation
Patch-Clamp Techniques
Potassium - chemistry
Potassium - metabolism
Potassium Channels, Inwardly Rectifying - physiology
Protein Isoforms
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases - biosynthesis
Protein-Serine-Threonine Kinases - metabolism
Rats
Rats, Sprague-Dawley
RNA, Messenger - metabolism
RNA, Small Interfering - metabolism
Small interfering RNA
Transfection
WNK Lysine-Deficient Protein Kinase 1
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:WNK kinases are serine-threonine kinases with an atypical placement of the catalytic lysine. Intronic deletions with increased expression of a ubiquitous long WNK1 transcript cause pseudohypoaldosteronism type 2 (PHA II), characterized by hypertension and hyperkalemia. Here, we report that long WNK1 inhibited ROMK1 by stimulating its endocytosis. Inhibition of ROMK by long WNK1 was synergistic with, but not dependent on, WNK4. A smaller transcript of WNK1 lacking the N-terminal 1-437 amino acids is expressed highly in the kidney. Whether expression of the KSWNK1 (kidney-specific, KS) is altered in PHA II is not known. We found that KS-WNK1 did not inhibit ROMK1 but reversed the inhibition of ROMK1 caused by long WNK1. Consistent with the lack of inhibition by KS-WNK1, we found that amino acids 1-491 of the long WNK1 were sufficient for inhibiting ROMK. Dietary K⁺ restriction decreases ROMK abundance in the renal cortical-collecting ducts by stimulating endocytosis, an adaptative response important for conservation of K⁺ during K⁺ deficiency. We found that K⁺ restriction in rats increased whole-kidney transcript of long WNK1 while decreasing that of KS-WNK1. Thus, KS-WNK1 is a physiological antagonist of long WNK1. Hyperkalemia in PHA II patients with PHA II mutations may be caused, at least partially, by increased expression of long WNK1 with or without decreased expression of KS-WNK1.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0510609103