ArticleThe Journal of biological chemistry2015
Na+ inhibits the epithelial Na+ channel by binding to a site in an extracellular acidic cleft.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed.
- Analysis of sodium self-inhibition of the epithelial sodium channel (ENaC) using classical and medium-throughput automated two-electrode voltage-clamp recordings.Pflugers Archiv : European journal of physiology · 2026Article
- Guinea pig δβγ-ENaC is locked in an open state and uncoupled from regulation by proteases.Pflugers Archiv : European journal of physiology · 2026Article
- The evolutionary path of the epithelial sodium channel δ-subunit in Cetartiodactyla points to a role in sodium sensing.Communications biology · 2025Article
- Structural insights into subunit-dependent functional regulation in epithelial sodium channels.Structure (London, England : 1993) · 2025Article
- Epithelial Na+ Channels, Immune Cells, and Salt.Annual review of physiology · 2025Review
- 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
- Mice lacking γENaC palmitoylation sites maintain benzamil-sensitive Na+ transport despite reduced channel activity.JCI insight · 2023Article
- Recording Sodium Self-Inhibition of Epithelial Sodium Channels Using Automated Electrophysiology inMembranes · 2023Article
- 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
- The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis.Biomedicines · 2022Review
- Accessibility of ENaC extracellular domain central core residues.The Journal of biological chemistry · 2022Article
- The Effect of Dynasore Upon the Negative Interaction Between ENaC and CFTR Channels in Xenopus laevis Oocytes.The Journal of membrane biology · 2022Article
- Hypertension and human immunodeficiency virus: A paradigm for epithelial sodium channels?Frontiers in cardiovascular medicine · 2022Review
- Two Functional Epithelial Sodium Channel Isoforms Are Present in Rodents despite Pronounced Evolutionary Pseudogenization and Exon Fusion.Molecular biology and evolution · 2021Article
- ENaC in Salt-Sensitive Hypertension: Kidney and Beyond.Current hypertension reports · 2020Review
- 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
- Oxidized Glutathione Increases Delta-Subunit Expressing Epithelial Sodium Channel Activity ineMedical research · 2020Article
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Authors and funding
5 authors.
Funding
Abstract
The epithelial Na(+) channel (ENaC) has a key role in the regulation of extracellular fluid volume and blood pressure. ENaC belongs to a family of ion channels that sense the external environment. These channels have large extracellular regions that are thought to interact with environmental cues, such as Na(+), Cl(-), protons, proteases, and shear stress, which modulate gating behavior. We sought to determine the molecular mechanism by which ENaC senses high external Na(+) concentrations, resulting in an inhibition of channel activity. Both our structural model of an ENaC α subunit and the resolved structure of an acid-sensing ion channel (ASIC1) have conserved acidic pockets in the periphery of the extracellular region of the channel. We hypothesized that these acidic pockets host inhibitory allosteric Na(+) binding sites. Through site-directed mutagenesis targeting the acidic pocket, we modified the inhibitory response to external Na(+). Mutations at selected sites altered the cation inhibitory preference to favor Li(+) or K(+) rather than Na(+). Channel activity was reduced in response to restraining movement within this region by cross-linking structures across the acidic pocket. Our results suggest that residues within the acidic pocket form an allosteric effector binding site for Na(+). Our study supports the hypothesis that an acidic cleft is a key ligand binding locus for ENaC and perhaps other members of the ENaC/degenerin family.
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