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.
J Biol Chem
2019 Jun 28;29426:10182-10193. doi: 10.1074/jbc.RA119.007394.
Show Gene links
Show Anatomy links
Murine epithelial sodium (Na+) channel regulation by biliary factors.
Wang XP, Im SJ, Balchak DM, Montalbetti N, Carattino MD, Ray EC, Kashlan OB.
???displayArticle.abstract???
The epithelial sodium channel (ENaC) mediates Na+ transport in several epithelia, including the aldosterone-sensitive distalnephron, distalcolon, and biliary epithelium. Numerous factors regulate ENaC activity, including extracellular ligands, post-translational modifications, and membrane-resident lipids. However, ENaC regulation by bile acids and conjugated bilirubin, metabolites that are abundant in the biliary tree and intestinal tract and are sometimes elevated in the urine of individuals with advanced liver disease, remains poorly understood. Here, using a Xenopus oocyte-based system to express and functionally study ENaC, we found that, depending on the bile acid used, bile acids both activate and inhibit mouse ENaC. Whether bile acids were activating or inhibiting was contingent on the position and orientation of specific bile acid moieties. For example, a hydroxyl group at the 12-position and facing the hydrophilic side (12α-OH) was activating. Taurine-conjugated bile acids, which have reduced membrane permeability, affected ENaC activity more strongly than did their more membrane-permeant unconjugated counterparts, suggesting that bile acids regulate ENaC extracellularly. Bile acid-dependent activation was enhanced by amino acid substitutions in ENaC that depress open probability and was precluded by proteolytic cleavage that increases open probability, consistent with an effect of bile acids on ENaC open probability. Bile acids also regulated ENaC in a cortical collecting duct cell line, mirroring the results in Xenopus oocytes. We also show that bilirubin conjugates activate ENaC. These results indicate that ENaC responds to compounds abundant in bile and that their ability to regulate this channel depends on the presence of specific functional groups.
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 Balchak,
The epithelial Na+ channel γ subunit autoinhibitory tract suppresses channel activity by binding the γ subunit's finger-thumb domain interface.
2018,
Pubmed
,
Xenbase Bohnert,
Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation and volume retention in nephrotic syndrome.
2018,
Pubmed
,
Xenbase Boscardin,
The function and regulation of acid-sensing ion channels (ASICs) and the epithelial Na(+) channel (ENaC): IUPHAR Review 19.
2016,
Pubmed Brandl,
Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis.
2018,
Pubmed Butterworth,
PKA-dependent ENaC trafficking requires the SNARE-binding protein complexin.
2005,
Pubmed
,
Xenbase Caldwell,
Serine protease activation of near-silent epithelial Na+ channels.
2004,
Pubmed 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,
Proteolytic processing of the epithelial sodium channel gamma subunit has a dominant role in channel activation.
2008,
Pubmed
,
Xenbase Cavanaugh,
Urine Sediment Examination in the Diagnosis and Management of Kidney Disease: Core Curriculum 2019.
2019,
Pubmed Chiang,
Bile acid metabolism and signaling.
2013,
Pubmed Enright,
Impact of Gut Microbiota-Mediated Bile Acid Metabolism on the Solubilization Capacity of Bile Salt Micelles and Drug Solubility.
2017,
Pubmed Frindt,
Na restriction activates epithelial Na channels in rat kidney through two mechanisms and decreases distal Na+ delivery.
2018,
Pubmed Frindt,
Responses of distal nephron Na+ transporters to acute volume depletion and hyperkalemia.
2017,
Pubmed Frindt,
Acute effects of aldosterone on the epithelial Na channel in rat kidney.
2015,
Pubmed Ghosh,
Airway hydration and COPD.
2015,
Pubmed Hernaez,
Acute-on-chronic liver failure: an update.
2017,
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 Ilyaskin,
Bile acids potentiate proton-activated currents in Xenopus laevis oocytes expressing human acid-sensing ion channel (ASIC1a).
2017,
Pubmed
,
Xenbase Ilyaskin,
Activation of the Human Epithelial Sodium Channel (ENaC) by Bile Acids Involves the Degenerin Site.
2016,
Pubmed
,
Xenbase Jiao,
Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD.
2018,
Pubmed Kabra,
Nedd4-2 induces endocytosis and degradation of proteolytically cleaved epithelial Na+ channels.
2008,
Pubmed Kashlan,
ENaC structure and function in the wake of a resolved structure of a family member.
2011,
Pubmed Kashlan,
Allosteric inhibition of the epithelial Na+ channel through peptide binding at peripheral finger and thumb domains.
2010,
Pubmed
,
Xenbase Kashlan,
Inhibitory tract traps the epithelial Na+ channel in a low activity conformation.
2012,
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 Kawamata,
A G protein-coupled receptor responsive to bile acids.
2003,
Pubmed Kleyman,
Epithelial Na+ Channel Regulation by Extracellular and Intracellular Factors.
2018,
Pubmed Koyama,
Induction of epithelial Na+ channel in rat ileum after proctocolectomy.
1999,
Pubmed Kunzelmann,
Electrolyte transport in the mammalian colon: mechanisms and implications for disease.
2002,
Pubmed Lapidus,
Gallbladder bile composition in patients with Crohn 's disease.
2006,
Pubmed Li,
Regulation of mechanosensitive biliary epithelial transport by the epithelial Na(+) channel.
2016,
Pubmed Makishima,
Identification of a nuclear receptor for bile acids.
1999,
Pubmed Memon,
Inherited disorders of bilirubin clearance.
2016,
Pubmed Miura,
Urinary bile acid sulfate levels in patients with primary biliary cirrhosis.
2011,
Pubmed Morimoto,
Mechanism underlying flow stimulation of sodium absorption in the mammalian collecting duct.
2006,
Pubmed
,
Xenbase Mueller,
Cys palmitoylation of the beta subunit modulates gating of the epithelial sodium channel.
2010,
Pubmed
,
Xenbase Mukherjee,
Cysteine palmitoylation of the γ subunit has a dominant role in modulating activity of the epithelial sodium channel.
2014,
Pubmed Mukherjee,
Specific Palmitoyltransferases Associate with and Activate the Epithelial Sodium Channel.
2017,
Pubmed
,
Xenbase Nesterov,
Trypsin can activate the epithelial sodium channel (ENaC) in microdissected mouse distal nephron.
2008,
Pubmed Noreng,
Structure of the human epithelial sodium channel by cryo-electron microscopy.
2018,
Pubmed Parks,
Bile acids: natural ligands for an orphan nuclear receptor.
1999,
Pubmed Passero,
Defining an inhibitory domain in the gamma subunit of the epithelial sodium channel.
2010,
Pubmed
,
Xenbase Patel,
Bile cast nephropathy: A case report and review of the literature.
2016,
Pubmed Pearce,
Collecting duct principal cell transport processes and their regulation.
2015,
Pubmed Roda,
Bile acid structure-activity relationship: evaluation of bile acid lipophilicity using 1-octanol/water partition coefficient and reverse phase HPLC.
1990,
Pubmed Rossier,
Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors.
2002,
Pubmed Schlattjan,
Regulation of renal tubular bile acid transport in the early phase of an obstructive cholestasis in the rat.
2003,
Pubmed Schmidt,
A Cytosolic Amphiphilic α-Helix Controls the Activity of the Bile Acid-sensitive Ion Channel (BASIC).
2016,
Pubmed
,
Xenbase Schmidt,
Modulation of DEG/ENaCs by Amphiphiles Suggests Sensitivity to Membrane Alterations.
2018,
Pubmed Sequeira,
Bile cast nephropathy: an often forgotten diagnosis.
2015,
Pubmed Simko,
Urinary bile acids in population screening for inapparent liver disease.
1998,
Pubmed Singal,
ACG Clinical Guideline: Alcoholic Liver Disease.
2018,
Pubmed Snyder,
Membrane topology of the amiloride-sensitive epithelial sodium channel.
1994,
Pubmed
,
Xenbase Soler,
Potassium status of patients with cirrhosis.
1976,
Pubmed Stockand,
Purinergic inhibition of ENaC produces aldosterone escape.
2010,
Pubmed Sullivan,
Diagnosis and evaluation of hyperbilirubinemia.
2017,
Pubmed Tetko,
Virtual computational chemistry laboratory--design and description.
2005,
Pubmed Toney,
Intrinsic control of sodium excretion in the distal nephron by inhibitory purinergic regulation of the epithelial Na(+) channel.
2012,
Pubmed Vallet,
An epithelial serine protease activates the amiloride-sensitive sodium channel.
1997,
Pubmed
,
Xenbase Wang,
Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.
1999,
Pubmed Wensing,
Urinary sodium balance in patients with cirrhosis: relationship to quantitative parameters of liver function.
1997,
Pubmed Wiemuth,
BASIC--a bile acid-sensitive ion channel highly expressed in bile ducts.
2012,
Pubmed Wiemuth,
Bile acids increase the activity of the epithelial Na+ channel.
2014,
Pubmed
,
Xenbase Wiemuth,
The bile acid-sensitive ion channel (BASIC), the ignored cousin of ASICs and ENaC.
2014,
Pubmed Wong,
Renal response to a saline load in well-compensated alcoholic cirrhosis.
1994,
Pubmed Wühr,
Deep proteomics of the Xenopus laevis egg using an mRNA-derived reference database.
2014,
Pubmed
,
Xenbase Yang,
Regulation of renal Na transporters in response to dietary K.
2018,
Pubmed
