ArticleThe Journal of clinical investigation1999
Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle's syndrome.
Article in The Journal of clinical investigation, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 125 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
125 citing papers in PubMed, 358 citations in OpenAlex.
- Adaptor-mediated interaction between Kv1.3 and Nedd4-2 E3 ubiquitin ligase.Communications biology · 2026Article
- Molecular Basis of Rare Inherited Tubulopathies of the Kidney: A Primer for Clinicians.International journal of molecular sciences · 2026Review
- Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies.Nature communications · 2025Article
- Investigating the role of the I-II linker in Nav1.5 channel function.The Journal of general physiology · 2025Article
- The ubiquitin ligase Nedd4-2 promotes localization of DNMBP/Tuba to P-bodies under hyperosmotic stress.The Journal of biological chemistry · 2025Article
- Differentially Expressed Nedd4-binding Protein Ndfip1 Protects Neurons Against Methamphetamine-induced Neurotoxicity.Neurotoxicity research · 2025Article
- Article
- The Epithelial Sodium Channel-An Underestimated Drug Target.International journal of molecular sciences · 2023Review
- Blood pressure effects of sodium transport along the distal nephron.Kidney international · 2022Review
- E3 ubiquitin ligase NEDD4L negatively regulates inflammation by promoting ubiquitination of MEKK2.EMBO reports · 2022Article
- Diacidic Motifs in the Carboxyl Terminus Are Required for ER Exit and Translocation to the Plasma Membrane of NKCC2.International journal of molecular sciences · 2022Article
- Gene and protein expression of dorsal root ganglion sensory receptors in normotensive and hypertensive male rats.American journal of physiology. Regulatory, integrative and comparative physiology · 2022Article
- Elevated intracellular NaProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Research progress of Nedd4L in cardiovascular diseases.Cell death discovery · 2022Review
- Does the early aldosterone-induced SGK1 play a role in early Kaliuresis?Physiological reports · 2022Article
- Mechanism of cargo sorting into small extracellular vesicles.Bioengineered · 2021Article
- Association of cystic fibrosis transmembrane conductance regulator with epithelial sodium channel subunits carrying Liddle's syndrome mutations.American journal of physiology. Lung cellular and molecular physiology · 2021Article
- Mechnetor: a web server for exploring protein mechanism and the functional context of genetic variants.Nucleic acids research · 2021Article
- Environmental circadian disruption suppresses rhythms in kidney function and accelerates excretion of renal injury markers in urine of male hypertensive rats.American journal of physiology. Renal physiology · 2021Article
- Article
65 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
Abstract
Liddle's syndrome is an inherited form of hypertension linked to mutations in the epithelial Na+ channel (ENaC). ENaC is composed of three subunits (alpha, beta, gamma), each containing a COOH-terminal PY motif (xPPxY). Mutations causing Liddle's syndrome alter or delete the PY motifs of beta- or gamma-ENaC. We recently demonstrated that the ubiquitin-protein ligase Nedd4 binds these PY motifs and that ENaC is regulated by ubiquitination. Here, we investigate, using the Xenopus oocyte system, whether Nedd4 affects ENaC function. Overexpression of wild-type Nedd4, together with ENaC, inhibited channel activity, whereas a catalytically inactive Nedd4 stimulated it, likely by acting as a competitive antagonist to endogenous Nedd4. These effects were dependant on the PY motifs, because no Nedd4-mediated changes in channel activity were observed in ENaC lacking them. The effect of Nedd4 on ENaC missing only one PY motif (of beta-ENaC), as originally described in patients with Liddle's syndrome, was intermediate. Changes were due entirely to alterations in ENaC numbers at the plasma membrane, as determined by surface binding and immunofluorescence. Our results demonstrate that Nedd4 is a negative regulator of ENaC and suggest that the loss of Nedd4 binding sites in ENaC observed in Liddle's syndrome may explain the increase in channel number at the cell surface, increased Na+ reabsorption by the distal nephron, and hence the hypertension.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.