Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
The epithelial Na+ channel (ENaC) is a member of the ENaC/degenerin family of ion channels. In the structure of a related family member, the "thumb" domain's base interacts with the pore, and its tip interacts with the divergent "finger" domain. Between the base and tip, the thumb domain is characterized by a conserved five-rung disulfide ladder holding together two anti-parallel α helices. The ENaC α and γ subunits' finger domains harbor autoinhibitory tracts that can be proteolytically liberated to activate the channel and also host an ENaC-specific pair of cysteines. Using a crosslinking approach, we show that one of the finger domain cysteines in the α subunit (αCys-263) and both of the finger domain cysteines in the γ subunit (γCys-213 and γCys-220) lie near the dynamic finger-thumb domain interface. Our data suggest that the αCys-256/αCys-263 pair is not disulfide-bonded. In contrast, we found that the γCys-213/γCys-220 pair is disulfide-bonded. Our data also suggest that the γ subunit lacks the terminal rung in the thumb domain disulfide ladder, suggesting asymmetry between the subunits. We also observed functional asymmetry between the α and γ subunit finger-thumb domain interfaces; crosslinks bridging the α subunit finger-thumb interface only inhibited ENaC currents, whereas crosslinks bridging the γ subunit finger-thumb interface activated or inhibited currents dependent on the length of the crosslinker. Our data suggest that reactive cysteines lie at the dynamic finger-thumb interfaces of the α and γ subunits and may play a yet undefined role in channel regulation.
Ahn,
Cloning and functional expression of the mouse epithelial sodium channel.
1999, Pubmed,
Xenbase
Ahn,
Cloning and functional expression of the mouse epithelial sodium channel.
1999,
Pubmed
,
Xenbase
Ben-Shahar,
Sensory functions for degenerin/epithelial sodium channels (DEG/ENaC).
2011,
Pubmed
Bruns,
Epithelial Na+ channels are fully activated by furin- and prostasin-dependent release of an inhibitory peptide from the gamma-subunit.
2007,
Pubmed
,
Xenbase
Canessa,
Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.
1994,
Pubmed
,
Xenbase
Carattino,
The epithelial Na+ channel is inhibited by a peptide derived from proteolytic processing of its alpha subunit.
2006,
Pubmed
,
Xenbase
Carattino,
Arachidonic acid regulates surface expression of epithelial sodium channels.
2003,
Pubmed
,
Xenbase
Carattino,
Defining an inhibitory domain in the alpha-subunit of the epithelial sodium channel.
2008,
Pubmed
,
Xenbase
Chen,
Gain-of-function variant of the human epithelial sodium channel.
2013,
Pubmed
,
Xenbase
Chen,
Mutations in the extracellular loop of alpha-rENaC alter sensitivity to amiloride and reactive species.
2004,
Pubmed
,
Xenbase
Chen,
External Cu2+ inhibits human epithelial Na+ channels by binding at a subunit interface of extracellular domains.
2011,
Pubmed
,
Xenbase
Collier,
Identification of epithelial Na+ channel (ENaC) intersubunit Cl- inhibitory residues suggests a trimeric alpha gamma beta channel architecture.
2011,
Pubmed
,
Xenbase
Collier,
Intersubunit conformational changes mediate epithelial sodium channel gating.
2014,
Pubmed
,
Xenbase
Downs,
H2O2 regulates lung epithelial sodium channel (ENaC) via ubiquitin-like protein Nedd8.
2013,
Pubmed
DuVall,
Peroxynitrite inhibits amiloride-sensitive Na+ currents in Xenopus oocytes expressing alpha beta gamma-rENaC.
1998,
Pubmed
,
Xenbase
Firsov,
Mutational analysis of cysteine-rich domains of the epithelium sodium channel (ENaC). Identification of cysteines essential for channel expression at the cell surface.
1999,
Pubmed
,
Xenbase
Guex,
SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling.
1997,
Pubmed
Haerteis,
The delta-subunit of the epithelial sodium channel (ENaC) enhances channel activity and alters proteolytic ENaC activation.
2009,
Pubmed
,
Xenbase
Haq,
Airway surface liquid homeostasis in cystic fibrosis: pathophysiology and therapeutic targets.
2016,
Pubmed
Hughey,
Epithelial sodium channels are activated by furin-dependent proteolysis.
2004,
Pubmed
,
Xenbase
Hughey,
Maturation of the epithelial Na+ channel involves proteolytic processing of the alpha- and gamma-subunits.
2003,
Pubmed
,
Xenbase
Jasti,
Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH.
2007,
Pubmed
Jeggle,
Atomic force microscopy imaging reveals the formation of ASIC/ENaC cross-clade ion channels.
2015,
Pubmed
Kapoor,
Interaction of ASIC1 and ENaC subunits in human glioma cells and rat astrocytes.
2011,
Pubmed
Kashlan,
Na+ inhibits the epithelial Na+ channel by binding to a site in an extracellular acidic cleft.
2015,
Pubmed
,
Xenbase
Kashlan,
Inhibitory tract traps the epithelial Na+ channel in a low activity conformation.
2012,
Pubmed
Kashlan,
ENaC structure and function in the wake of a resolved structure of a family member.
2011,
Pubmed
Kashlan,
Constraint-based, homology model of the extracellular domain of the epithelial Na+ channel α subunit reveals a mechanism of channel activation by proteases.
2011,
Pubmed
Kashlan,
Allosteric inhibition of the epithelial Na+ channel through peptide binding at peripheral finger and thumb domains.
2010,
Pubmed
,
Xenbase
Kobashi,
Catalytic oxidation of sulfhydryl groups by o-phenanthroline copper complex.
1968,
Pubmed
Köckerling,
Electrogenic Na+ absorption of rat distal colon is confined to surface epithelium: a voltage-scanning study.
1993,
Pubmed
Li,
Asymmetric organization of the pore region of the epithelial sodium channel.
2003,
Pubmed
,
Xenbase
Ma,
Hydrogen peroxide stimulates the epithelial sodium channel through a phosphatidylinositide 3-kinase-dependent pathway.
2011,
Pubmed
,
Xenbase
Maarouf,
Novel determinants of epithelial sodium channel gating within extracellular thumb domains.
2009,
Pubmed
,
Xenbase
Mall,
CFTR-mediated inhibition of epithelial Na+ conductance in human colon is defective in cystic fibrosis.
1999,
Pubmed
Passero,
Defining an inhibitory domain in the gamma subunit of the epithelial sodium channel.
2010,
Pubmed
,
Xenbase
Pearce,
Collecting duct principal cell transport processes and their regulation.
2015,
Pubmed
Ray,
Human epithelial Na+ channel missense variants identified in the GenSalt study alter channel activity.
2016,
Pubmed
,
Xenbase
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Schild,
Identification of amino acid residues in the alpha, beta, and gamma subunits of the epithelial sodium channel (ENaC) involved in amiloride block and ion permeation.
1997,
Pubmed
,
Xenbase
Sheng,
Extracellular histidine residues crucial for Na+ self-inhibition of epithelial Na+ channels.
2004,
Pubmed
,
Xenbase
Sheng,
Functional role of extracellular loop cysteine residues of the epithelial Na+ channel in Na+ self-inhibition.
2007,
Pubmed
,
Xenbase
Snyder,
A pore segment in DEG/ENaC Na(+) channels.
1999,
Pubmed
Trac,
Alveolar nonselective channels are ASIC1a/α-ENaC channels and contribute to AFC.
2017,
Pubmed
Xu,
ENaC alpha-subunit variants are expressed in lung epithelial cells and are suppressed by oxidative stress.
2007,
Pubmed
,
Xenbase
