Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter.
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Human NTCP cDNA encodes a 349-residue glycoprotein that, when expressed in Xenopus oocytes, mediates saturable Na+-dependent taurocholate uptake with apparent Km ~6 uM.
"Saturation kinetics indicated that the human NTCP has a higher affinity for taurocholate (apparent Km = 6 microM) than the previously cloned rat protein (apparent Km = 25 microM)."
Homo- and hetero-dimeric architecture of the human liver Na⁺-dependent taurocholate co-transporting protein.
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NTCP forms dimers that persist at the plasma membrane, and reducing plasma-membrane NTCP abundance reduces NTCP-mediated taurocholate uptake.
"FRET (fluorescence resonance energy transfer) using fluorescently labelled subunits further demonstrated that dimerization persists at the plasma membrane."
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NTCP forms heteromeric complexes with other SLC10 family members in vitro.
"SLC10A4 and SLC10A6 co-immunoprecipitated with NTCP, demonstrating that heteromeric complexes can be formed between SLC10A family members in vitro."
Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition.
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NTCP is the key transporter for hepatic uptake of bile acids from the portal circulation; the S267F variant loses bile acid uptake while retaining estrone sulfate transport, separating the two substrate classes.
"exhibited a near complete loss of function for bile acid uptake yet fully normal transport function for the non-bile acid substrate estrone sulfate"
Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter.
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The liver Na+-bile acid cotransporter is multispecific and may participate in hepatic clearance of organic anion metabolites and xenobiotics, in contrast to the narrow specificity of the ileal/renal transporter.
"Whereas the multispecific liver Na(+)-bile acid cotransporter may participate in
hepatic clearance of organic anion metabolites and xenobiotics, the ileal and
renal Na(+)-bile acid cotransporter retains a narrow specificity for reclamation
of bile acids."
Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype.
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SLC10A1 is the major transporter of conjugated bile salts from plasma into the hepatocyte; the R252H patient variant fails to reach the plasma membrane and causes extreme plasma hypercholanemia without cholestatic liver disease.
"Immunofluorescence studies and surface biotinylation experiments demonstrated that the mutant protein is virtually absent from the plasma membrane."
Functional and Pharmacological Comparison of Human and Mouse Na(+)/Taurocholate Cotransporting Polypeptide (NTCP).
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NTCP is located in the basolateral membrane of hepatocytes and transports bile acids from portal blood into hepatocytes; human NTCP also transports the drug rosuvastatin.
"The Na+/taurocholate cotransporting polypeptide (NTCP) is located in the basolateral membrane of hepatocytes, where it transports bile acids from the portal blood back into hepatocytes."
Structural basis of sodium-dependent bile salt uptake into the liver.
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Cryo-EM structures of human NTCP reveal a gated-pore transport mechanism; the open-to-outside state exposes the determinant residues for HBV/HDV preS1 binding.
"NTCP undergoes a conformational
transition opening a wide transmembrane pore that serves as the transport
pathway for bile salts, and exposes key determinant residues for HBV/HDV binding
to the outside of the cell."
Structure of the bile acid transporter and HBV receptor NTCP.
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Establishing HBV infection requires interaction between the large viral envelope glycoprotein LHBs and the host entry receptor NTCP, a sodium-dependent bile acid transporter.
"For HBV infection to be established, a molecular interaction is required between the large glycoproteins
of the virus envelope (known as LHBs) and the host entry receptor sodium
taurocholate co-transporting polypeptide (NTCP), a sodium-dependent bile acid
transporter from the blood to hepatocytes"
Structural insights into the HBV receptor and bile acid transporter NTCP.
Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus.
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The preS1 receptor-binding region cross-links specifically to NTCP; NTCP silencing inhibits HBV/HDV infection and ectopic NTCP expression confers susceptibility on non-susceptible hepatoma cells.
"Silencing NTCP inhibited HBV and HDV infection, while exogenous
NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to
these viral infections."
Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology.
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NTCP deficiency presents with extremely elevated plasma bile salts (up to 1,500 uM) but without jaundice, pruritus or liver dysfunction.
"The most prominent biochemical feature was the extremely elevated total bile salt level in plasma (up to 1,500"
A reference map of the human binary protein interactome.
The solute carrier superfamily interactome.
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity.
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
Combined Automated Annotation using Multiple IEA Methods.
SLC10A1 co-transport bile salts and Na+ from extracellular region to cytosol
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A bile salt and two sodium ions are transported into the cytosol by NTCP in the plasma membrane.
"A molecule of extracellular bile salt (glyco- or taurocholate, or glyco- or taurochenodeoxycholate) and two sodium ions are transported into the cytosol, mediated by NTCP (Na+ / taurocholate cotransporter) in the plasma membrane."
Recycling of bile acids and salts