Slc10a1 (Ntcp, Na+/taurocholate cotransporting polypeptide) is the principal sodium-dependent bile salt uptake carrier of the mouse liver. It is a 362-residue multi-pass membrane protein of the bile acid:sodium symporter (BASS, TC 2.A.28) family that resides in the basolateral (sinusoidal) plasma membrane of hepatocytes, where it imports conjugated and unconjugated bile salts from portal blood into the hepatocyte in co-transport with two sodium ions, driven by the inward sodium gradient [PMID:10209268, PMID:34060352]. Transport is strictly dependent on extracellular sodium and is saturable, with the liver-dominant isoform showing an apparent Km near 86 uM for taurocholate and an alternatively spliced, C-terminally shortened isoform showing roughly sixfold higher affinity [PMID:10209268]. Substrate scope is broad for a bile salt carrier and extends to non-bile-acid organic anions such as estrone-3-sulfate and to drugs including rosuvastatin, with kinetics and inhibitor sensitivity closely matching the human orthologue [PMID:34060352]. By performing the hepatocyte uptake step, Slc10a1 is one of the central transporters of enterohepatic bile salt cycling, and loss of its hepatic expression impairs portal bile acid uptake and raises plasma bile acid concentrations [PMID:11279518]. Unlike human NTCP, the mouse protein does not act as a functional entry receptor for hepatitis B or hepatitis D virus; it binds the preS1 lipopeptide and retains full symport activity, but it cannot support infection, a restriction that maps to residues 84-87 in the first extracellular loop and is reversed by replacing them with their human counterparts [PMID:23678176].
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Mouse Ntcp is a multi-pass plasma membrane transporter; the whole-family PANTHER node PTN000040759 correctly places plasma-membrane residence across the SLC10 family, and mouse Ntcp functions there [PMID:34060352]. Reason: The ancestral node placement is appropriate, since every characterized SLC10 member acts at the plasma membrane, and the target has its own direct evidence of surface transport activity, so it is plainly inside the clade that inherited the localization. UniProt also records Cell membrane, multi-pass, for O08705. The term is a parent of the more specific GO:0016323 that this gene also carries, which is acceptable redundancy rather than an error. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000040759 SUPPORTS TRANSFER Family-wide ancestral node for plasma-membrane residence; mouse Ntcp descends from it and acts at the cell surface. RGD:3681 · Slc10a1 SUPPORTS TRANSFER Rat orthologue with IDA plasma-membrane and basolateral annotations; closest donor to the target. UniProtKB:Q14973 · SLC10A1 SUPPORTS TRANSFER Human orthologue, IDA plasma membrane from PMID:22029531. RGD:3682 · Slc10a2 SUPPORTS TRANSFER Rat paralog (apical ileal ASBT); a legitimate co-descendant seed for the generic plasma-membrane node even though its polarity differs. MGI:MGI:1201406 · Slc10a2 SUPPORTS TRANSFER Mouse paralog; same reasoning as RGD:3682. UniProtKB:Q96EP9 · SLC10A4 SUPPORTS TRANSFER Human paralog; contributes only to the generic plasma-membrane node, which is all the term asserts. Supporting Evidence: PMID:34060352 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. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic mapping of the UniProt subcellular location Cell membrane (SL-0039) for O08705 to GO:0005886, which is correct for this transporter [PMID:34060352]. Reason: The source UniProt annotation (Cell membrane, multi-pass membrane protein) is accurate, and the vocabulary-to-GO mapping is a faithful one-to-one translation. The term is less specific than the basolateral annotations the gene also carries, but a correct broader electronic parent is harmless. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 · Cell membrane SUPPORTS TRANSFER Controlled-vocabulary location on the O08705 record itself; the mapping to GO:0005886 is exact. Supporting Evidence: PMID:34060352 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. |
| GO:0005886 plasma membrane | ISO GO_REF:0000119 | ACCEPT | Summary: Orthology transfer of the human SLC10A1 plasma-membrane localization, which rests on an IDA in PMID:22029531, and the mouse protein is likewise a surface transporter [PMID:34060352]. Reason: The donor annotation is experimental rather than itself propagated, the orthology between O08705 and Q14973 is unambiguous (one-to-one, both the liver bile salt uptake carrier), and the mouse protein has independent evidence of functioning at the hepatocyte basolateral surface. Mouse Ntcp having its own direct functional data does not make this transfer circular, because the donor is an IDA, so there is no transfer-of-a-transfer anywhere in the chain. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q14973 · SLC10A1 SUPPORTS TRANSFER Human orthologue with IDA plasma-membrane annotation (PMID:22029531); experimentally grounded donor, not a propagation. Supporting Evidence: PMID:34060352 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. |
| GO:0008508 bile acid:sodium symporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Sodium-coupled bile salt symport is the defining activity of the NTCP/ASBT clade, and mouse Ntcp performs it directly, with both splice isoforms mediating saturable Na+-dependent taurocholate uptake in oocytes [PMID:10209268]. Reason: This is the core molecular function of the gene. The IBD node PTN000040761 sits on the clade that contains both the hepatic (NTCP) and ileal (ASBT) sodium-dependent bile acid cotransporters, which is exactly where the activity arose, and mouse Ntcp is inside it. The node placement is independently confirmed on the target, since mouse Ntcp transports taurocholate in a strictly sodium-dependent, saturable manner, and UniProt curates the two-sodium-per-bile-salt reaction (RHEA:71875) from the same paper. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000040761 SUPPORTS TRANSFER Ancestral node for sodium-coupled bile acid symport in the NTCP/ASBT clade; correct placement for this activity, and mouse Ntcp descends from it. RGD:3681 · Slc10a1 SUPPORTS TRANSFER Rat orthologue, IDA GO:0008508 from PMID:1961729; one of the descendant evidences behind the node. RGD:3682 · Slc10a2 SUPPORTS TRANSFER Rat ileal ASBT paralog; shares the symport chemistry and is a valid co-descendant seed for this node, differing only in localization and substrate breadth. Supporting Evidence: PMID:10209268 Both isoforms mediated saturable Na+-dependent transport of taurocholate when expressed in Xenopus laevis oocytes. PMID:23678176 In addition, mNTCP can mediate taurocholate uptake in the presence of sodium as efficient as hNTCP |
| GO:0008508 bile acid:sodium symporter activity | ISO GO_REF:0000096 | ACCEPT | Summary: Mouse-rat orthology transfer of the rat Ntcp IDA for sodium-coupled bile acid symport (PMID:1961729), independently confirmed on the mouse protein [PMID:10209268]. Reason: The donor is the rat orthologue with a direct-assay annotation for the same term, and the mouse protein has been shown in the same kind of assay to do the same thing, so the transfer is both well grounded and correct. It is not redundant with the IBA row, because the IBA asserts inheritance from the clade node while this row asserts orthology-level equivalence to the rat protein, and duplicate terms under different evidence codes are acceptable. Propagation Review Root cause: NO FAILURE CORE Sources checked: RGD:3681 · Slc10a1 SUPPORTS TRANSFER Rat orthologue with IDA GO:0008508 (PMID:1961729); experimentally grounded, not a propagation. Supporting Evidence: PMID:10209268 Both isoforms mediated saturable Na+-dependent transport of taurocholate when expressed in Xenopus laevis oocytes. |
| GO:0015125 bile acid transmembrane transporter activity | ISO GO_REF:0000096 | ACCEPT | Summary: Orthology transfer from rat Ntcp, whose bile acid transporter activity is an IDA (PMID:15297262), and mouse Ntcp transports taurocholate, cholate and other bile salts [PMID:10209268, PMID:34060352]. Reason: Correct, though less informative than the GO:0008508 annotation the gene also carries, since it omits the sodium coupling. Both granularities are retained because the parent is true and the child adds the mechanism, so no replacement term is needed. The rat donor annotation is experimental. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: RGD:3681 · Slc10a1 SUPPORTS TRANSFER Rat orthologue with IDA GO:0015125 (PMID:15297262). Sound donor; the only caveat is that the transferred term is the sodium-agnostic parent of the gene's GO:0008508 annotation. Supporting Evidence: PMID:10209268 Both isoforms mediated saturable Na+-dependent transport of taurocholate when expressed in Xenopus laevis oocytes. |
| GO:0015125 bile acid transmembrane transporter activity | ISO GO_REF:0000119 | ACCEPT | Summary: The same bile acid transporter activity transferred from the human orthologue, where it is an IDA (PMID:22029531), and human and mouse NTCP have closely matching transport kinetics in a side-by-side comparison [PMID:34060352]. Reason: The human donor annotation is experimental, the orthology is one-to-one, and the only published head-to-head functional comparison of the two proteins found similar Km values for a shared substrate and a shared drug substrate, which is about as direct a validation of a cross-species transfer as is available. Duplication with the rat-sourced ISO row for the same term is acceptable. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q14973 · SLC10A1 SUPPORTS TRANSFER Human orthologue with IDA GO:0015125 (PMID:22029531); the transfer is corroborated by the direct human-mouse functional comparison in PMID:34060352. Supporting Evidence: PMID:34060352 a functional comparison of human NTCP (hNTCP) and mouse Ntcp (mNtcp) showed similar Km values of 67 ± 10 µM and 104 ± 9 µM for the probe substrate estrone-3-sulfate as well as of 258 ± 42 µM and 199 ± 13 µM for the drug rosuvastatin, respectively. |
| GO:0015721 bile acid and bile salt transport | IBA GO_REF:0000033 | ACCEPT | Summary: Mouse Ntcp executes the hepatocyte uptake step of bile salt transport, the process term matching its symporter activity, and loss of its hepatic expression impairs portal bile acid uptake in vivo [PMID:11279518]. Reason: The participation requirement is met directly rather than by a necessity argument, because the protein itself translocates the bile salt across the membrane and so performs a step of the process. The IBD node is the same clade node that carries the symporter activity, which is the right place for it, and in mouse liver reduced Slc10a1 expression measurably reduces portal bile acid uptake. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000040761 SUPPORTS TRANSFER Same ancestral node as the symporter activity; bile acid transport is the process that activity constitutes, so the node placement is consistent. RGD:3681 · Slc10a1 SUPPORTS TRANSFER Rat orthologue, IDA GO:0015721 from PMID:1961729. RGD:3682 · Slc10a2 SUPPORTS TRANSFER Rat ileal ASBT paralog; also a bile acid transporter, so a valid co-descendant seed for this process node. Supporting Evidence: PMID:11279518 Tcf1-/- liver has decreased expression of the basolateral membrane bile acid transporters Slc10a1, Slc21a3 and Slc21a5, leading to impaired portal bile acid uptake and elevated plasma bile acid concentrations. PMID:34060352 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. |
| GO:0015721 bile acid and bile salt transport | ISO GO_REF:0000096 | ACCEPT | Summary: Mouse-rat orthology transfer of the rat Ntcp IDA for bile acid and bile salt transport (PMID:1961729); the mouse protein performs the same uptake step at the hepatocyte basolateral membrane [PMID:11279518, PMID:34060352]. Reason: The donor annotation is experimental and the function it describes is the gene's defining physiological role in both species. The transfer is not a substitute for direct evidence in mouse but is consistent with it, and no divergence between rat and mouse bile salt uptake has been reported. Propagation Review Root cause: NO FAILURE CORE Sources checked: RGD:3681 · Slc10a1 SUPPORTS TRANSFER Rat orthologue with IDA GO:0015721 (PMID:1961729); experimentally grounded donor. Supporting Evidence: PMID:11279518 Tcf1-/- liver has decreased expression of the basolateral membrane bile acid transporters Slc10a1, Slc21a3 and Slc21a5, leading to impaired portal bile acid uptake and elevated plasma bile acid concentrations. |
| GO:0016020 membrane | IDA PMID:11279518 Hepatocyte nuclear factor-1alpha is an essential regulator o... | MODIFY | Summary: MGI IDA placing mouse Slc10a1 in a membrane, from the Hnf1a study in which Slc10a1 is characterized as one of the basolateral membrane bile acid transporters of mouse liver [PMID:11279518]. Reason: The localization claim is right but the term is uninformative for a direct-assay annotation, since GO:0016020 is the root of the membrane branch and says nothing about which membrane. The cited paper itself places Slc10a1 in the basolateral membrane of the hepatocyte, and that assignment is corroborated by the side-by-side functional study of mouse and human NTCP, so the annotation should be deepened to GO:0016323 basolateral plasma membrane rather than removed. The cached record is abstract-only, so the curator's underlying assay detail is not visible here, and this MODIFY therefore sharpens the term without disputing the observation. Proposed replacements: basolateral plasma membrane Supporting Evidence: PMID:11279518 Tcf1-/- liver has decreased expression of the basolateral membrane bile acid transporters Slc10a1, Slc21a3 and Slc21a5, leading to impaired portal bile acid uptake and elevated plasma bile acid concentrations. PMID:34060352 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. |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic membrane annotation from the bile acid:sodium symporter domain signature (InterPro IPR002657) plus an ARBA rule; mouse Ntcp is indeed a multi-pass membrane protein. Reason: The domain-to-term mapping is correct, since every member of this family is an integral membrane transporter, and a broad electronic parent of the gene's correctly annotated plasma-membrane and basolateral children is harmless. No action is needed on an IEA merely for being less specific than the manual annotations alongside it. This deliberately differs from the MODIFY assigned to the IDA row for the same term, because a direct-assay localization should name the membrane it observed, whereas a family-signature inference genuinely cannot resolve polarity and is therefore correctly stated at the broad level. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR002657 · Bile acid:sodium symporter SUPPORTS TRANSFER Correct family signature for O08705; supports membrane residence but cannot resolve which membrane. ARBA:ARBA00028763 SUPPORTS TRANSFER Automatic rule consistent with the family signature; adds no specificity beyond it. Supporting Evidence: PMID:34060352 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. |
| GO:0016323 basolateral plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: NTCP-specific PANTHER node placing the hepatic bile salt uptake carrier on the basolateral (sinusoidal) hepatocyte membrane, where mouse Ntcp acts [PMID:34060352, PMID:11279518]. Reason: This is the most informative and best-placed of the localization annotations. PTN002570905 is a sub-node restricted to the NTCP branch, so it correctly excludes the apical ileal ASBT paralogs whose polarity is the opposite, which is precisely the discrimination a naive family-wide transfer would get wrong. The target is inside that branch, and the assignment matches the mouse data, since Ntcp takes up bile acids from portal blood and that requires sinusoidal exposure. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002570905 SUPPORTS TRANSFER NTCP-specific ancestral node; the restriction to this sub-clade is what makes the basolateral call correct rather than a family-wide over-propagation. RGD:3681 · Slc10a1 SUPPORTS TRANSFER Rat orthologue with IDA basolateral plasma membrane annotations (PMID:15297262, PMID:17082223). Supporting Evidence: PMID:34060352 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. PMID:11279518 Tcf1-/- liver has decreased expression of the basolateral membrane bile acid transporters Slc10a1, Slc21a3 and Slc21a5, leading to impaired portal bile acid uptake and elevated plasma bile acid concentrations. |
| GO:0016323 basolateral plasma membrane | ISO GO_REF:0000096 | ACCEPT | Summary: Mouse-rat orthology transfer of the rat Ntcp IDA basolateral localization; mouse Ntcp occupies the same hepatocyte domain [PMID:34060352]. Reason: The donor annotation is an IDA on the rat orthologue and the localization is functionally required in mouse as well, since uptake is from portal blood at the sinusoidal face. There is no evidence of polarity divergence between rodent orthologues, and the duplication with the IBA and ISS rows for the same term is acceptable. Propagation Review Root cause: NO FAILURE CORE Sources checked: RGD:3681 · Slc10a1 SUPPORTS TRANSFER Rat orthologue with IDA GO:0016323 (PMID:15297262, PMID:17082223); experimentally grounded donor. Supporting Evidence: PMID:34060352 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. |
| GO:0016323 basolateral plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-judged sequence-similarity transfer of the rat Ntcp (P26435) basolateral localization to the mouse protein, which is the same assignment reached independently by the IBA and ISO routes. Reason: The source is the rat orthologue, whose basolateral localization is experimentally determined, and rat-mouse Ntcp orthology is unambiguous. The conclusion agrees with the mouse-specific literature, so the weaker ISS evidence code does not make the annotation wrong; it is simply the least informative of three concordant routes to the same term. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P26435 · Slc10a1 SUPPORTS TRANSFER Rat orthologue; UniProt-side counterpart of the RGD:3681 donor, with the same IDA grounding for basolateral localization. Supporting Evidence: PMID:34060352 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. |
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Download this section (compressed HTML)Q: Mouse Ntcp has a clean direct-assay functional characterization (saturable, sodium-dependent taurocholate uptake for both splice isoforms in PMID:10209268; kinetics and inhibitor profile in PMID:34060352), yet all transport annotations on O08705 are ISO or IBA. Should MGI add direct experimental annotations for GO:0008508 and GO:0015721 from these papers, so the mouse record no longer depends entirely on orthology transfer?
Q: The two splice isoforms differ roughly sixfold in taurocholate affinity (Km 14 uM for the shortened isoform 2 versus 86 uM for isoform 1, PMID:10209268), but no isoform-resolved annotation exists. Is an isoform-qualified annotation warranted, or is a kinetic difference without a distinct activity outside what GO records?
Q: Mouse Ntcp transports estrone-3-sulfate and the drug rosuvastatin in transfected cells (PMID:34060352). Should this be captured as a process annotation such as xenobiotic transport, as the substrate scope of the transporter activity via has_input extensions, or not at all given that the evidence comes from heterologous overexpression?
Q: Mouse Ntcp binds the HBV preS1 lipopeptide but cannot support HBV or HDV entry (PMID:23678176). Is there any GO representation for a binding-competent but non-functional receptor homologue, or is the correct curation simply to assert nothing, and should a taxon constraint or a NOT annotation be considered to block future automated transfer of GO:0001618 and GO:0046718 from human SLC10A1?
Experiment: Hepatocyte-specific conditional Slc10a1 knockout mice with quantitative bile salt flux measurements (portal-venous extraction, plasma and biliary bile acid pools) to establish the in vivo contribution of Ntcp to the uptake step, separating it from the sodium-independent Oatp-mediated route that may compensate in mouse.
Experiment: Isoform-resolved rescue of Slc10a1-null hepatocytes with Ntcp1 versus Ntcp2 to test whether the higher-affinity shortened isoform makes a distinguishable physiological contribution, and whether the C-terminal segment governs trafficking or regulation rather than catalysis.
Experiment: Side-by-side proteoliposome reconstitution of mouse and human NTCP to measure sodium stoichiometry and substrate turnover for bile salts, sulfated steroids and drug substrates under identical conditions, putting the cross-species orthology transfers on a quantitative footing.
Experiment: Structure determination of mouse Ntcp and of the humanized mNtcp-h84-87 variant, with paired preS1 binding and entry assays, to resolve how the first extracellular loop converts a binding-competent transporter into a functional viral receptor while leaving symport unchanged.
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