ArticleThe Journal of biological chemistry2009
Novel determinants of epithelial sodium channel gating within extracellular thumb domains.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed.
- Acid-sensing ion channel 2a assembles with epithelial NaThe Journal of biological chemistry · 2026Article
- Epithelial NaComprehensive Physiology · 2024Review
- The Epithelial Sodium Channel-An Underestimated Drug Target.International journal of molecular sciences · 2023Review
- Accessibility of ENaC extracellular domain central core residues.The Journal of biological chemistry · 2022Article
- Hypertension: Do Inflammation and Immunity Hold the Key to Solving this Epidemic?Circulation research · 2021Review
- Regulating ENaC's gate.American journal of physiology. Cell physiology · 2020Review
- Analyses of epithelial NaThe Journal of biological chemistry · 2019Article
- New insights regarding epithelial Na+ channel regulation and its role in the kidney, immune system and vasculature.Current opinion in nephrology and hypertension · 2019Review
- Thumb domains of the three epithelial NaThe Journal of biological chemistry · 2018Article
- The epithelial NaThe Journal of biological chemistry · 2018Article
- Conserved cysteines in the finger domain of the epithelial NaThe Journal of biological chemistry · 2018Article
- Epithelial NaAnnual review of physiology · 2018Review
- Regulation of the epithelial NaThe Journal of biological chemistry · 2017Article
- Human epithelial Na+ channel missense variants identified in the GenSalt study alter channel activity.American journal of physiology. Renal physiology · 2016Article
- The Epithelial Sodium Channel and the Processes of Wound Healing.BioMed research international · 2016Review
- Pseudohypoaldosteronism type 1 and Liddle's syndrome mutations that affect the single-channel properties of the epithelial Na+ channel.Physiological reports · 2015Article
- Functional Roles of Clusters of Hydrophobic and Polar Residues in the Epithelial Na+ Channel Knuckle Domain.The Journal of biological chemistry · 2015Article
- Na+ inhibits the epithelial Na+ channel by binding to a site in an extracellular acidic cleft.The Journal of biological chemistry · 2015Article
- Cysteine palmitoylation of the γ subunit has a dominant role in modulating activity of the epithelial sodium channel.The Journal of biological chemistry · 2014Article
- Article
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Authors and funding
9 authors.
Funding
Abstract
Activity of the epithelial Na(+) channel (ENaC) is modulated by Na(+) self-inhibition, an allosteric down-regulation of channel open probability by extracellular Na(+). We searched for determinants of Na(+) self-inhibition by analyzing changes in this inhibitory response resulting from specific mutations within the extracellular domains of mouse ENaC subunits. Mutations at gammaMet(438) altered the Na(+) self-inhibition response in a substitution-specific manner. Fourteen substitutions (Ala, Arg, Asp, Cys, Gln, Glu, His, Ile, Phe, Pro, Ser, Thr, Tyr, and Val) significantly suppressed Na(+) self-inhibition, whereas three mutations (Asn, Gly, and Leu) moderately enhanced the inhibition. Met to Lys mutation did not alter Na(+) self-inhibition. Mutations at the homologous site in the alpha subunit (G481A, G481C, and G481M) dramatically increased the magnitude and speed of Na(+) self-inhibition. Mutations at the homologous betaAla(422) resulted in minimal or no change in Na(+) self-inhibition. Low, high, and intermediate open probabilities were observed in oocytes expressing alphaG481Mbetagamma, alphabetagammaM438V, and alphaG481M/betagammaM438V, respectively. This pair of residues map to thealpha5 helix in the extracellular thumb domain in the chicken acid sensing ion channel 1 structure. Both residues likely reside near the channel surface because both alphaG481Cbetagamma and alphabetagammaM438C channels were inhibited by an externally applied and membrane-impermeant sulfhydryl reagent. Our results demonstrate that alphaGly(481) and gammaMet(438) are functional determinants of Na(+) self-inhibition and of ENaC gating and suggest that the thumb domain contributes to the channel gating machinery.
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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.