ArticleThe Journal of general physiology2014
Intersubunit conformational changes mediate epithelial sodium channel gating.
Article in The Journal of general physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- The small molecule activator S3969 stimulates the epithelial sodium channel by interacting with a specific binding pocket in the channel's β-subunit.The Journal of biological chemistry · 2024Article
- Epithelial NaComprehensive Physiology · 2024Review
- Recording Sodium Self-Inhibition of Epithelial Sodium Channels Using Automated Electrophysiology inMembranes · 2023Article
- Transmembrane serine protease 2 (TMPRSS2) proteolytically activates the epithelial sodium channel (ENaC) by cleaving the channel's γ-subunit.The Journal of biological chemistry · 2022Article
- Accessibility of ENaC extracellular domain central core residues.The Journal of biological chemistry · 2022Article
- Probing conformational changes during activation of ASIC1a by an optical tweezer and by methanethiosulfonate-based cross-linkers.PloS one · 2022Article
- Molecular principles of assembly, activation, and inhibition in epithelial sodium channel.eLife · 2020Article
- Regulation of ion transport from within ion transit pathways.The Journal of general physiology · 2020Review
- Analyses of epithelial NaThe Journal of biological chemistry · 2019Article
- An extracellular acidic cleft confers profound HThe Journal of biological chemistry · 2019Article
- Thumb domains of the three epithelial NaThe Journal of biological chemistry · 2018Article
- The epithelial NaThe Journal of biological chemistry · 2018Article
- Article
- Conserved cysteines in the finger domain of the epithelial NaThe Journal of biological chemistry · 2018Article
- Epithelial transport inThe Journal of general physiology · 2017Review
- Cytokine-Ion Channel Interactions in Pulmonary Inflammation.Frontiers in immunology · 2017Review
- Restoration of Epithelial Sodium Channel Function by Synthetic Peptides in Pseudohypoaldosteronism Type 1B Mutants.Frontiers in pharmacology · 2017Article
- The Lectin-like Domain of TNF Increases ENaC Open Probability through a Novel Site at the Interface between the Second Transmembrane and C-terminal Domains of the α-Subunit.The Journal of biological chemistry · 2016Article
- Exploration of the Peptide Recognition of an Amiloride-sensitive FMRFamide Peptide-gated Sodium Channel.The Journal of biological chemistry · 2016Article
- Gain-of-Function Mutation W493R in the Epithelial Sodium Channel Allosterically Reconfigures Intersubunit Coupling.The Journal of biological chemistry · 2016Article
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Authors and funding
5 authors.
Funding
Abstract
The epithelial Na(+) channel (ENaC) functions as a pathway for Na(+) absorption in the kidney and lung, where it is crucial for Na(+) homeostasis and blood pressure regulation. However, the basic mechanisms that control ENaC gating are poorly understood. Here we define a role in gating for residues forming interfaces between the extracellular domains of the three ENaC subunits. Using cysteine substitution combined with chemical cross-linking, we determined that residues located at equivalent positions in the three subunits (αK477, βE446, and γE455) form interfaces with residues in adjacent subunits (βV85, γV87, and αL120, respectively). Cross-linking of these residues altered ENaC activity in a length-dependent manner; long cross-linkers increased ENaC current by increasing its open probability, whereas short cross-linkers reduced ENaC open probability. Cross-linking also disrupted ENaC gating responses to extracellular pH and Na(+), signals which modulate ENaC activity during shifts in volume status. Introduction of charged side chains at the interfacing residues altered ENaC activity in a charge-dependent manner. Current increased when like charges were present at both interfacing residues, whereas opposing charges reduced current. Together, these data indicate that conformational changes at intersubunit interfaces participate in ENaC transitions between the open and closed states; movements that increase intersubunit distance favor the open state, whereas the closed state is favored when the distance is reduced. This provides a mechanism to modulate ENaC gating in response to changing extracellular conditions that threaten Na(+) homeostasis.
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