ArticleThe Journal of biological chemistry2012
Identification of extracellular domain residues required for epithelial Na+ channel activation by acidic pH.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- Varying Selection Pressure for a Na+ Sensing Site in Epithelial Na+ Channel Subunits Reflect Divergent Roles in Na+ Homeostasis.Molecular biology and evolution · 2024Article
- Epithelial NaComprehensive Physiology · 2024Review
- Accessibility of ENaC extracellular domain central core residues.The Journal of biological chemistry · 2022Article
- Atomic Force Microscopy (AFM) Applications in Arrhythmogenic Cardiomyopathy.International journal of molecular sciences · 2022Review
- Analyses of epithelial NaThe Journal of biological chemistry · 2019Article
- An extracellular acidic cleft confers profound HThe Journal of biological chemistry · 2019Article
- The epithelial NaThe Journal of biological chemistry · 2018Article
- Incorporation of the δ-subunit into the epithelial sodium channel (ENaC) generates protease-resistant ENaCs inThe Journal of biological chemistry · 2018Article
- Review
- The role of pendrin in blood pressure regulation.American journal of physiology. Renal physiology · 2016Review
- Na+ inhibits the epithelial Na+ channel by binding to a site in an extracellular acidic cleft.The Journal of biological chemistry · 2015Article
- Intersubunit conformational changes mediate epithelial sodium channel gating.The Journal of general physiology · 2014Article
- Article
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Authors and funding
5 authors at 1 institution in 1 country.
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Abstract
A growing body of evidence suggests that the extracellular domain of the epithelial Na(+) channel (ENaC) functions as a sensor that fine tunes channel activity in response to changes in the extracellular environment. We previously found that acidic pH increases the activity of human ENaC, which results from a decrease in Na(+) self-inhibition. In the current work, we identified extracellular domain residues responsible for this regulation. We found that rat ENaC is less sensitive to pH than human ENaC, an effect mediated in part by the γ subunit. We identified a group of seven residues in the extracellular domain of γENaC (Asp-164, Gln-165, Asp-166, Glu-292, Asp-335, His-439, and Glu-455) that, when individually mutated to Ala, decreased proton activation of ENaC. γ(E455) is conserved in βENaC (Glu-446); mutation of this residue to neutral amino acids (Ala, Cys) reduced ENaC stimulation by acidic pH, whereas reintroduction of a negative charge (by MTSES modification of Cys) restored pH regulation. Combination of the seven γENaC mutations with β(E446A) generated a channel that was not activated by acidic pH, but inhibition by alkaline pH was intact. Moreover, these mutations reduced the effect of pH on Na(+) self-inhibition. Together, the data identify eight extracellular domain residues in human β- and γENaC that are required for regulation by acidic pH.
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