ArticleThe Journal of physiology2010
A mutation of the epithelial sodium channel associated with atypical cystic fibrosis increases channel open probability and reduces Na+ self inhibition.
Article in The Journal of physiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed.
- Acute activation of human epithelial sodium channel (ENaC) by serum and glucocorticoid inducible kinase 1 (SGK1) requires prior cleavage of the channel's γ-subunit at its proximal cleavage site.Pflugers Archiv : European journal of physiology · 2025Article
- Epithelial NaComprehensive Physiology · 2024Review
- Design and Synthesis of Novel Squaraine-Based Fluorescent Probe for Far-Red Detection of Chymotrypsin Enzyme.Molecules (Basel, Switzerland) · 2024Article
- Effects of the environment on the evolution of the vertebrate urinary tract.Nature reviews. Urology · 2023Review
- The Epithelial Sodium Channel-An Underestimated Drug Target.International journal of molecular sciences · 2023Review
- Cystic Fibrosis Screen Positive, Inconclusive Diagnosis Genotypes in People with Cystic Fibrosis from the U.S. Patient Registry.Annals of the American Thoracic Society · 2023Article
- Kidney ion handling genes and their interaction in blood pressure control.Bioscience reports · 2022Review
- The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis.Biomedicines · 2022Review
- Regulation of distal tubule sodium transport: mechanisms and roles in homeostasis and pathophysiology.Pflugers Archiv : European journal of physiology · 2022Review
- COVID-19 and Liquid Homeostasis in the Lung-A Perspective through the Epithelial Sodium Channel (ENaC) Lens.Cells · 2022Review
- Accessibility of ENaC extracellular domain central core residues.The Journal of biological chemistry · 2022Article
- Activation by cleavage of the epithelial NaeLife · 2022Article
- A polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts.Journal of cell science · 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
- Engineered mutant α-ENaC subunit mRNA delivered by lipid nanoparticles reduces amiloride currents in cystic fibrosis-based cell and mice models.Science advances · 2020Article
- Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies.Pharmaceutics · 2020Review
- Paraoxonase 3 functions as a chaperone to decrease functional expression of the epithelial sodium channel.The Journal of biological chemistry · 2020Article
- Effects of syntaxins 2, 3, and 4 on rat and human epithelial sodium channel (ENaC) in Xenopus laevis oocytes.Pflugers Archiv : European journal of physiology · 2020Article
- Regulating ENaC's gate.American journal of physiology. Cell physiology · 2020Review
- Analyses of epithelial NaThe Journal of biological chemistry · 2019Article
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Increased activity of the epithelial sodium channel (ENaC) in the respiratory airways contributes to the pathophysiology of cystic fibrosis (CF), a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In some patients suffering from atypical CF a mutation can be identified in only one CFTR allele. We recently identified in this group of CF patients a heterozygous mutation (W493R) in the alpha-subunit of ENaC. Here, we investigate the functional effects of this mutation by expressing wild-type alpha beta gamma ENaC or mutant alpha(W493R)beta gamma ENaC in Xenopus oocytes. The alpha W493R mutation stimulated amiloride-sensitive whole-cell currents (Delta I(ami)) by approximately 4-fold without altering the single-channel conductance or surface expression of ENaC. As these data suggest that the open probability (P(o)) of the mutant channel is increased, we investigated the proteolytic activation of ENaC by chymotrypsin. Single-channel recordings revealed that chymotrypsin activated near-silent channels in outside-out membrane patches from oocytes expressing wild-type ENaC, but not in membrane patches from oocytes expressing the mutant channel. In addition, the alpha W493R mutation abolished Na(+) self inhibition of ENaC, which might also contribute to its gain-of-function effects. We conclude that the alpha W493R mutation promotes constitutive activation of ENaC by reducing the inhibitory effect of extracellular Na(+) and decreasing the pool of near-silent channels. The resulting gain-of-function phenotype of the mutant channel might contribute to the pathophysiology of CF in patients carrying this mutation.
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