Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms

Ahmed Lazrak; Zhen Liu; Chou-Long Huang

doi:10.1073/pnas.0510609103

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Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms

Journal article

Open access

Peer reviewed

Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms

Ahmed Lazrak, Zhen Liu and Chou-Long Huang

Proceedings of the National Academy of Sciences - PNAS, Vol.103(5), pp.1615-1620

01/31/2006

DOI: 10.1073/pnas.0510609103

PMCID: PMC1360592

PMID: 16428287

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Abstract

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 KS-WNK1 (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.

Amino Acid Sequence

Animals

Blotting, Western

Cell Line

Clathrin - metabolism

DNA - chemistry

DNA - metabolism

Dose-Response Relationship, Drug

Dynamins - metabolism

Electrophysiology

Endocytosis

Exons

Female

Gene Expression Regulation

Green Fluorescent Proteins - metabolism

Humans

Immunoprecipitation

Intracellular Signaling Peptides and Proteins

Kidney - metabolism

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

Transfection

WNK Lysine-Deficient Protein Kinase 1

Details

Title: Subtitle: Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms
Creators: Ahmed Lazrak - The University of Texas Southwestern Medical Center
Zhen Liu - The University of Texas Southwestern Medical Center
Chou-Long Huang - Internal Medicine
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.103(5), pp.1615-1620
DOI: 10.1073/pnas.0510609103
PMID: 16428287
PMCID: PMC1360592
ISSN: 0027-8424
eISSN: 1091-6490
Grant note: R01 DK059530 / NIDDK NIH HHS DK 54368 / NIDDK NIH HHS R01 DK054368 / NIDDK NIH HHS DK 59530-S1 / NIDDK NIH HHS DK 59530 / NIDDK NIH HHS
Language: English
Date published: 01/31/2006
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984359813002771

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