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.
Activation of the Human Epithelial Sodium Channel (ENaC) by Bile Acids Involves the Degenerin Site.
Ilyaskin AV
,
Diakov A
,
Korbmacher C
,
Haerteis S
.
???displayArticle.abstract???
The epithelial sodium channel (ENaC) is a member of the ENaC/degenerin ion channel family, which also includes the bile acid-sensitive ion channel (BASIC). So far little is known about the effects of bile acids on ENaC function. ENaC is probably a heterotrimer consisting of three well characterized subunits (αβγ). In humans, but not in mice and rats, an additional δ-subunit exists. The aim of this study was to investigate the effects of chenodeoxycholic, cholic, and deoxycholic acid in unconjugated (CDCA, CA, and DCA) and tauro-conjugated (t-CDCA, t-CA, t-DCA) form on human ENaC in its αβγ- and δβγ-configuration. We demonstrated that tauro-conjugated bile acids significantly stimulate ENaC in the αβγ- and in the δβγ-configuration. In contrast, non-conjugated bile acids have a robust stimulatory effect only on δβγENaC. Bile acids stimulate ENaC-mediated currents by increasing the open probability of active channels without recruiting additional near-silent channels known to be activated by proteases. Stimulation of ENaC activity by bile acids is accompanied by a significant reduction of the single-channel current amplitude, indicating an interaction of bile acids with a region close to the channel pore. Analysis of the known ASIC1 (acid-sensing ion channel) crystal structure suggested that bile acids may bind to the pore region at the degenerin site of ENaC. Substitution of a single amino acid residue within the degenerin region of βENaC (N521C or N521A) significantly reduced the stimulatory effect of bile acids on ENaC, suggesting that this site is critical for the functional interaction of bile acids with the channel.
Adams,
Protons activate brain Na+ channel 1 by inducing a conformational change that exposes a residue associated with neurodegeneration.
1998, Pubmed,
Xenbase
Adams,
Protons activate brain Na+ channel 1 by inducing a conformational change that exposes a residue associated with neurodegeneration.
1998,
Pubmed
,
Xenbase
Alvarez de la Rosa,
Structure and regulation of amiloride-sensitive sodium channels.
2000,
Pubmed
Caldwell,
Serine protease activation of near-silent epithelial Na+ channels.
2004,
Pubmed
Caldwell,
Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport.
2005,
Pubmed
Canessa,
Structural biology: unexpected opening.
2007,
Pubmed
Chalfie,
The identification and suppression of inherited neurodegeneration in Caenorhabditis elegans.
1990,
Pubmed
Collier,
Extracellular protons regulate human ENaC by modulating Na+ self-inhibition.
2009,
Pubmed
,
Xenbase
Diakov,
A novel pathway of epithelial sodium channel activation involves a serum- and glucocorticoid-inducible kinase consensus motif in the C terminus of the channel's alpha-subunit.
2004,
Pubmed
,
Xenbase
Diakov,
Cleavage in the {gamma}-subunit of the epithelial sodium channel (ENaC) plays an important role in the proteolytic activation of near-silent channels.
2008,
Pubmed
,
Xenbase
Diakov,
Protein kinase B alpha (PKBα) stimulates the epithelial sodium channel (ENaC) heterologously expressed in Xenopus laevis oocytes by two distinct mechanisms.
2010,
Pubmed
,
Xenbase
Driscoll,
The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration.
1991,
Pubmed
Firsov,
Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: a quantitative approach.
1996,
Pubmed
,
Xenbase
Garty,
Epithelial sodium channels: function, structure, and regulation.
1997,
Pubmed
Giraldez,
Cloning and functional expression of a new epithelial sodium channel delta subunit isoform differentially expressed in neurons of the human and monkey telencephalon.
2007,
Pubmed
,
Xenbase
Giraldez,
ENaC in the brain--future perspectives and pharmacological implications.
2013,
Pubmed
Haerteis,
An inhibitory peptide derived from the α-subunit of the epithelial sodium channel (ENaC) shows a helical conformation.
2012,
Pubmed
,
Xenbase
Haerteis,
Proteolytic activation of the human epithelial sodium channel by trypsin IV and trypsin I involves distinct cleavage sites.
2014,
Pubmed
,
Xenbase
Haerteis,
Plasmin and chymotrypsin have distinct preferences for channel activating cleavage sites in the γ subunit of the human epithelial sodium channel.
2012,
Pubmed
,
Xenbase
Haerteis,
Proteolytic activation of the epithelial sodium channel (ENaC) by the cysteine protease cathepsin-S.
2012,
Pubmed
,
Xenbase
Haerteis,
The delta-subunit of the epithelial sodium channel (ENaC) enhances channel activity and alters proteolytic ENaC activation.
2009,
Pubmed
,
Xenbase
Helenius,
Solubilization of membranes by detergents.
1975,
Pubmed
Hill,
Endogenously expressed epithelial sodium channel is present in lipid rafts in A6 cells.
2002,
Pubmed
Hill,
The epithelial sodium channel (ENaC) traffics to apical membrane in lipid rafts in mouse cortical collecting duct cells.
2007,
Pubmed
,
Xenbase
Hylemon,
Bile acids as regulatory molecules.
2009,
Pubmed
Jasti,
Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH.
2007,
Pubmed
Ji,
Degenerin sites mediate proton activation of deltabetagamma-epithelial sodium channel.
2004,
Pubmed
,
Xenbase
Kellenberger,
Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure.
2002,
Pubmed
Kellenberger,
An external site controls closing of the epithelial Na+ channel ENaC.
2002,
Pubmed
,
Xenbase
Kellenberger,
Permeability properties of ENaC selectivity filter mutants.
2001,
Pubmed
,
Xenbase
Kellenberger,
A single point mutation in the pore region of the epithelial Na+ channel changes ion selectivity by modifying molecular sieving.
1999,
Pubmed
,
Xenbase
Kellenberger,
On the molecular basis of ion permeation in the epithelial Na+ channel.
1999,
Pubmed
,
Xenbase
Kellenberger,
International Union of Basic and Clinical Pharmacology. XCI. structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel.
2015,
Pubmed
Korbmacher,
A calcium-activated and nucleotide-sensitive nonselective cation channel in M-1 mouse cortical collecting duct cells.
1995,
Pubmed
Krueger,
Cholesterol depletion of the plasma membrane prevents activation of the epithelial sodium channel (ENaC) by SGK1.
2009,
Pubmed
,
Xenbase
Lefèvre,
Pharmacological and electrophysiological characterization of the human bile acid-sensitive ion channel (hBASIC).
2014,
Pubmed
Li,
Regulation of mechanosensitive biliary epithelial transport by the epithelial Na(+) channel.
2016,
Pubmed
Loffing,
Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC).
2009,
Pubmed
Lorenz,
Heteromultimeric CLC chloride channels with novel properties.
1996,
Pubmed
,
Xenbase
Lundbaek,
Lipid bilayer regulation of membrane protein function: gramicidin channels as molecular force probes.
2010,
Pubmed
Mano,
Bioconversion of 3beta-hydroxy-5-cholenoic acid into chenodeoxycholic acid by rat brain enzyme systems.
2004,
Pubmed
Mello-Vieira,
Cytotoxic bile acids, but not cytoprotective species, inhibit the ordering effect of cholesterol in model membranes at physiologically active concentrations.
2013,
Pubmed
Rossier,
Epithelial sodium channel (ENaC) and the control of blood pressure.
2014,
Pubmed
Rossier,
Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors.
2002,
Pubmed
Sakai,
Cloning and functional expression of a novel degenerin-like Na+ channel gene in mammals.
1999,
Pubmed
,
Xenbase
Schaefer,
Molecular cloning, functional expression and chromosomal localization of an amiloride-sensitive Na(+) channel from human small intestine.
2000,
Pubmed
,
Xenbase
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
Schmidt,
The bile acid-sensitive ion channel (BASIC) is activated by alterations of its membrane environment.
2014,
Pubmed
,
Xenbase
Sheng,
Epithelial sodium channel pore region. structure and role in gating.
2001,
Pubmed
,
Xenbase
Snyder,
The epithelial Na+ channel: cell surface insertion and retrieval in Na+ homeostasis and hypertension.
2002,
Pubmed
Snyder,
Gating induces a conformational change in the outer vestibule of ENaC.
2000,
Pubmed
,
Xenbase
Snyder,
A pore segment in DEG/ENaC Na(+) channels.
1999,
Pubmed
Stewart,
Atomic force microscopy reveals the architecture of the epithelial sodium channel (ENaC).
2011,
Pubmed
,
Xenbase
Stockand,
Insight toward epithelial Na+ channel mechanism revealed by the acid-sensing ion channel 1 structure.
2008,
Pubmed
Tavernarakis,
Molecular modeling of mechanotransduction in the nematode Caenorhabditis elegans.
1997,
Pubmed
Thomsen,
MolDock: a new technique for high-accuracy molecular docking.
2006,
Pubmed
Waldmann,
Molecular cloning and functional expression of a novel amiloride-sensitive Na+ channel.
1995,
Pubmed
,
Xenbase
Waldmann,
The human degenerin MDEG, an amiloride-sensitive neuronal cation channel, is localized on chromosome 17q11.2-17q12 close to the microsatellite D17S798.
1996,
Pubmed
Wesch,
The neuronal-specific SGK1.1 kinase regulates {delta}-epithelial Na+ channel independently of PY motifs and couples it to phospholipase C signaling.
2010,
Pubmed
,
Xenbase
West,
Modulation of basal and peptide hormone-stimulated Na transport by membrane cholesterol content in the A6 epithelial cell line.
2005,
Pubmed
,
Xenbase
Wiemuth,
Bile acids increase the activity of the epithelial Na+ channel.
2014,
Pubmed
,
Xenbase
Wiemuth,
BASIC--a bile acid-sensitive ion channel highly expressed in bile ducts.
2012,
Pubmed
Yamamura,
Epithelial Na+ channel delta subunit mediates acid-induced ATP release in the human skin.
2008,
Pubmed
Yamamura,
Capsazepine is a novel activator of the delta subunit of the human epithelial Na+ channel.
2004,
Pubmed
,
Xenbase
Yamamura,
Icilin activates the delta-subunit of the human epithelial Na+ channel.
2005,
Pubmed
,
Xenbase
Zhou,
Bile acids modulate signaling by functional perturbation of plasma membrane domains.
2013,
Pubmed
