flvcr2a encodes zebrafish MFSD7c/FLVCR2A, a multi-pass membrane transporter that mediates choline transmembrane transport at the blood-brain barrier, with additional reported ethanolamine and heme transport activities and localization to plasma, endoplasmic-reticulum, and mitochondrial membranes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0015232 heme transmembrane transporter activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: heme transmembrane transporter activity (GO:0015232) is retained cautiously as a historical/contested inferred context but is not the current core function. The heme-import model derives from 2010 hemin-binding and heme-analog uptake assays in heterologous systems, whereas 2024 structural and physiological work de-orphanizes FLVCR2/MFSD7c as a choline/ethanolamine transporter and notes that FLVCR2-mediated heme uptake has not been confirmed. Reason: UniProt now emphasizes choline transport at the BBB and describes heme transport only as an additional/by-similarity activity. The falcon deep research synthesis treats heme transport as an older, less secure hypothesis superseded by direct choline-transport evidence; it is retained as non-core pending direct zebrafish testing. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt ethanolamine (By similarity) file:DANRE/flvcr2a/flvcr2a-uniprot.txt heme b transporter (By similarity) file:DANRE/flvcr2a/flvcr2a-deep-research-falcon.md Earlier literature proposed **heme import** by FLVCR2 based on hemin-binding and heme-analog uptake assays file:DANRE/flvcr2a/flvcr2a-deep-research-falcon.md The 2024 Nature paper explicitly notes that **FLVCR2-mediated heme uptake “has not been confirmed”** |
| GO:0016020 membrane | IBA GO_REF:0000033 | REMOVE | Summary: membrane (GO:0016020) is too broad and should not be modified across GO aspects. Reason: Specific membrane locations are reviewed separately; this generic CC annotation should be retired rather than replaced with MF/BP transport terms. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000858822 · MFSD7/FLVCR2 MFS transporter family node SUPPORTS TRANSFER Membrane residence is real, but the generic membrane term is uninformative and is superseded by the specific cell-membrane/transporter localization reviewed separately. UniProtKB:Q9UPI3 · human FLVCR2/MFSD7c donor SUPPORTS TRANSFER Donor supports membrane residence; specific cell membrane location is preferred. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Choline uniporter that specifically mediates choline uptake file:DANRE/flvcr2a/flvcr2a-uniprot.txt Reaction=choline(out) = choline(in) file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane PMID:38302740 MFSD7c is a choline transporter at the blood-brain barrier |
| GO:0020037 heme binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: heme binding (GO:0020037) is retained cautiously as a historical/contested inferred heme context but is not the current core function. Historical support comes from 2010 hemin-agarose binding assays for FLVCR2; 2024 work reframes the FLVCR2/MFSD7c family around choline/ethanolamine transport. Reason: UniProt now emphasizes choline transport at the BBB and describes heme transport only as an additional/by-similarity activity; the falcon synthesis treats heme binding/transport as a legacy hypothesis not confirmed in current mechanistic work. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt ethanolamine (By similarity) file:DANRE/flvcr2a/flvcr2a-uniprot.txt heme b transporter (By similarity) file:DANRE/flvcr2a/flvcr2a-deep-research-falcon.md Earlier literature proposed **heme import** by FLVCR2 based on hemin-binding and heme-analog uptake assays |
| GO:0097037 heme export | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: heme export (GO:0097037) is retained cautiously as a historical/contested inferred heme context but is not the current core function. 2024 mechanistic work concludes FLVCR2-mediated heme uptake has not been confirmed and prioritizes choline/ethanolamine as the primary transported substrates. Reason: UniProt now emphasizes choline transport at the BBB and describes heme transport only as an additional/by-similarity activity; heme export is retained as a legacy hypothesis pending direct zebrafish testing. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt ethanolamine (By similarity) file:DANRE/flvcr2a/flvcr2a-uniprot.txt heme b transporter (By similarity) file:DANRE/flvcr2a/flvcr2a-deep-research-falcon.md The 2024 Nature paper explicitly notes that **FLVCR2-mediated heme uptake “has not been confirmed”** |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: endoplasmic reticulum membrane (GO:0005789) is supported as an inferred membrane location but is not the primary functional site for the choline transporter annotation. Reason: The core choline transporter role is best tied to plasma membrane/BBB context. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Endoplasmic reticulum membrane file:DANRE/flvcr2a/flvcr2a-uniprot.txt Mitochondrion membrane file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: plasma membrane (GO:0005886) is supported for Flvcr2a/MFSD7c. Reason: Current evidence supports MFSD7c as a choline transporter at the blood-brain barrier/plasma membrane. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Choline uniporter that specifically mediates choline uptake file:DANRE/flvcr2a/flvcr2a-uniprot.txt Reaction=choline(out) = choline(in) file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane PMID:38302740 MFSD7c is a choline transporter at the blood-brain barrier |
| GO:0015220 choline transmembrane transporter activity | IEA GO_REF:0000117 | ACCEPT | Summary: choline transmembrane transporter activity (GO:0015220) is supported for Flvcr2a/MFSD7c. Reason: Current evidence supports MFSD7c as a choline transporter at the blood-brain barrier/plasma membrane. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Choline uniporter that specifically mediates choline uptake file:DANRE/flvcr2a/flvcr2a-uniprot.txt Reaction=choline(out) = choline(in) file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane PMID:38302740 MFSD7c is a choline transporter at the blood-brain barrier |
| GO:0015871 choline transport | IEA GO_REF:0000108 | ACCEPT | Summary: choline transport (GO:0015871) is supported for Flvcr2a/MFSD7c. Reason: Current evidence supports MFSD7c as a choline transporter at the blood-brain barrier/plasma membrane. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Choline uniporter that specifically mediates choline uptake file:DANRE/flvcr2a/flvcr2a-uniprot.txt Reaction=choline(out) = choline(in) file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane PMID:38302740 MFSD7c is a choline transporter at the blood-brain barrier |
| GO:0022857 transmembrane transporter activity | IEA GO_REF:0000002 | MODIFY | Summary: transmembrane transporter activity (GO:0022857) is too broad for Flvcr2a. The specific function is choline transmembrane transporter activity, with mechanistic evidence that the FLVCR2/MFSD7c family operates as a facilitative uniporter driving downhill transport independent of sodium or pH gradients, with substrate selectivity mediated by conserved aromatic (cation-pi) residues. Reason: The supported molecular function should be the specific choline transmembrane transporter activity; 2024 structural/transport work defines the FLVCR2 family as uniporters rather than coupled/ATP-driven pumps. Proposed replacements: choline transmembrane transporter activity Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Choline uniporter that specifically mediates choline uptake file:DANRE/flvcr2a/flvcr2a-uniprot.txt Reaction=choline(out) = choline(in) file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane PMID:38302740 MFSD7c is a choline transporter at the blood-brain barrier file:DANRE/flvcr2a/flvcr2a-deep-research-falcon.md both operate as **uniporters** file:DANRE/flvcr2a/flvcr2a-deep-research-falcon.md downhill transport independent of sodium or pH gradients |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: mitochondrial membrane (GO:0031966) is supported as an inferred membrane location but is not the primary functional site for the choline transporter annotation. Reason: The core choline transporter role is best tied to plasma membrane/BBB context. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Endoplasmic reticulum membrane file:DANRE/flvcr2a/flvcr2a-uniprot.txt Mitochondrion membrane file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane |
| GO:0034229 ethanolamine transport | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: ethanolamine transport (GO:0034229) is supported by similarity as a secondary/conditional transported substrate. In MFSD7c-focused assays ethanolamine uptake was not increased by MFSD7c alone but became significant when ethanolamine kinase (ETNK1) was co-expressed (metabolic trapping); human FLVCR2 structural work independently supports choline and ethanolamine as the transported solutes. Reason: The best-supported zebrafish/core role is choline transport; ethanolamine transport is retained as non-core substrate context, supported but more conditional than choline in MFSD7c-specific data. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt ethanolamine (By similarity) file:DANRE/flvcr2a/flvcr2a-uniprot.txt heme b transporter (By similarity) file:DANRE/flvcr2a/flvcr2a-deep-research-falcon.md MFSD7c did not increase ethanolamine uptake alone, but ethanolamine transport became significant when **ethanolamine kinase (ETNK1)** was co-expressed |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | MODIFY | Summary: transmembrane transport (GO:0055085) is too broad for Flvcr2a. Reason: The supported biological process should be the specific choline transport process. Proposed replacements: choline transport Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Choline uniporter that specifically mediates choline uptake file:DANRE/flvcr2a/flvcr2a-uniprot.txt Reaction=choline(out) = choline(in) file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane PMID:38302740 MFSD7c is a choline transporter at the blood-brain barrier |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: endoplasmic reticulum membrane (GO:0005789) is supported as an inferred membrane location but is not the primary functional site for the choline transporter annotation. Reason: The core choline transporter role is best tied to plasma membrane/BBB context. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Endoplasmic reticulum membrane file:DANRE/flvcr2a/flvcr2a-uniprot.txt Mitochondrion membrane file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: plasma membrane (GO:0005886) is supported for Flvcr2a/MFSD7c and is the functional site of choline transport. Transport assays for human/mouse MFSD7c rely on plasma-membrane localization, and a transport-deficient disease mutant (S203Y) retained normal plasma-membrane localization, indicating its defect reflects functional impairment rather than mislocalization. Reason: Current evidence supports MFSD7c as a choline transporter at the blood-brain barrier/plasma membrane, with plasma-membrane localization confirmed in heterologous transport assays. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Choline uniporter that specifically mediates choline uptake file:DANRE/flvcr2a/flvcr2a-uniprot.txt Reaction=choline(out) = choline(in) file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane PMID:38302740 MFSD7c is a choline transporter at the blood-brain barrier file:DANRE/flvcr2a/flvcr2a-deep-research-falcon.md a transport-deficient mutant (S203Y) was stated not to have defective plasma membrane localization |
| GO:0031966 mitochondrial membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: mitochondrial membrane (GO:0031966) is supported as an inferred membrane location but is not the primary functional site for the choline transporter annotation. Reason: The core choline transporter role is best tied to plasma membrane/BBB context. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Endoplasmic reticulum membrane file:DANRE/flvcr2a/flvcr2a-uniprot.txt Mitochondrion membrane file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane |
| GO:0034228 ethanolamine transmembrane transporter activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ethanolamine transmembrane transporter activity (GO:0034228) is supported by similarity as a secondary transported substrate. A 2024 Nature study concludes that human FLVCR1 and FLVCR2 mediate cellular transport of choline and ethanolamine, supporting ethanolamine as a bona fide FLVCR2-family substrate while choline remains the best-supported activity for MFSD7c. Reason: The best-supported zebrafish/core role is choline transport; ethanolamine transport is retained as non-core substrate context, strongly supported for human FLVCR2 in structural/transport assays. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt ethanolamine (By similarity) file:DANRE/flvcr2a/flvcr2a-uniprot.txt heme b transporter (By similarity) file:DANRE/flvcr2a/flvcr2a-deep-research-falcon.md A 2024 Nature study concludes that human **FLVCR1 and FLVCR2 mediate cellular transport of choline and ethanolamine** |
| GO:0015220 choline transmembrane transporter activity | IDA PMID:38302740 MFSD7c functions as a transporter of choline at the blood-br... | ACCEPT | Summary: choline transmembrane transporter activity (GO:0015220) is the core molecular function of Flvcr2a/MFSD7c. Critically, the zebrafish orthologs themselves were directly tested: the two zebrafish MFSD7c isoforms (DaMfsd7c_a, DaMfsd7c_b) show choline transport activity in heterologous assays, providing direct species-relevant support rather than inference alone. 2024 mechanistic work establishes the transporter operates as a facilitative uniporter mediating concentration-driven (downhill) choline movement. Reason: Current evidence supports MFSD7c as a choline transporter at the blood-brain barrier/plasma membrane, with direct transport activity demonstrated for the zebrafish orthologs. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Choline uniporter that specifically mediates choline uptake file:DANRE/flvcr2a/flvcr2a-uniprot.txt Reaction=choline(out) = choline(in) file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane PMID:38302740 MFSD7c is a choline transporter at the blood-brain barrier file:DANRE/flvcr2a/flvcr2a-deep-research-falcon.md zebrafish MFSD7c isoforms “DaMfsd7c_a” and “DaMfsd7c_b” show choline transport activity in heterologous assays file:DANRE/flvcr2a/flvcr2a-deep-research-falcon.md zebrafish isoforms a and b also showed choline transport activity |
| GO:0150104 transport across blood-brain barrier | ISS GO_REF:0000024 | ACCEPT | Summary: transport across blood-brain barrier (GO:0150104) is supported for Flvcr2a/MFSD7c. In mammals, endothelial-specific Mfsd7c knockout reduces brain uptake of injected radiolabeled choline while peripheral organ signals remain comparable, and the transporter is expressed in CNS endothelial/BBB cells. For zebrafish this is a conservation-based (ISS) inference; direct in vivo zebrafish BBB choline-flux data are not yet available. Reason: Current evidence supports MFSD7c as a choline transporter at the blood-brain barrier/plasma membrane, consistent with mammalian endothelial knockout reducing brain choline import. Retained as a conservation-based inference for zebrafish. Supporting Evidence: file:DANRE/flvcr2a/flvcr2a-uniprot.txt Choline uniporter that specifically mediates choline uptake file:DANRE/flvcr2a/flvcr2a-uniprot.txt Reaction=choline(out) = choline(in) file:DANRE/flvcr2a/flvcr2a-uniprot.txt Cell membrane PMID:38302740 MFSD7c is a choline transporter at the blood-brain barrier file:DANRE/flvcr2a/flvcr2a-deep-research-falcon.md loss of MFSD7c reduces brain uptake of injected radiolabeled choline while leaving peripheral organ signals comparable |
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Download this section (compressed HTML)Q: Does zebrafish flvcr2a transport choline at the blood-brain barrier with the same facilitative, electrogenic mechanism demonstrated for mammalian MFSD7c, and is it required for brain choline homeostasis in zebrafish?
Q: Is the heme-transport activity inferred from FLVCR-family orthologs functionally relevant for zebrafish flvcr2a, or has this paralog specialized for choline and ethanolamine transport?
Experiment: Express zebrafish flvcr2a in a cultured cell line and measure radiolabeled choline uptake and single-cell patch-clamp currents to test for facilitative, electrogenic choline transport.
Hypothesis: Zebrafish flvcr2a mediates facilitative, electrogenic choline uptake, like its mammalian ortholog MFSD7c.
Experiment: Generate a flvcr2a zebrafish mutant and perform metabolomic profiling of choline-related metabolites in brain versus other tissues, and assess cerebral vasculature.
Hypothesis: Loss of flvcr2a disrupts brain choline homeostasis in zebrafish, modeling Fowler syndrome.
Experiment: Test recombinant flvcr2a in a heme b transport/export assay and compare its activity with that of a bona fide heme transporter.
Hypothesis: Zebrafish flvcr2a does not contribute substantial heme transport in vivo despite FLVCR-family homology.
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