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Megalin-mediated endocytosis of transcobalamin-vitamin-B12 complexes suggests a role of the receptor in vitamin-B12 homeostasis.
Open accessAbstract
Kidney cortex is a main target for circulating vitamin B12 (cobalamin) in complex with transcobalamin (TC). Ligand blotting of rabbit kidney cortex with rabbit 125I-TC-B12 and human TC-57Co-B12 revealed an exclusive binding to megalin, a 600-kDa endocytic receptor present in renal proximal tubule epithelium and other absorptive epithelia. The binding was Ca2+ dependent and inhibited by receptor-associated protein (RAP). Surface plasmon resonance analysis demonstrated a high-affinity interaction between purified rabbit megalin and rabbit TC-B12 but no measurable affinity of the vitamin complex for the homologous alpha 2-macroglobulin receptor (alpha 2MR)/low density lipoprotein receptor related protein (LRP). 125I-TC-B12 was efficiently endocytosed in a RAP-inhibitable manner in megalin-expressing rat yolk sac carcinoma cells and in vivo microperfused rat proximal tubules. The radioactivity in the tubules localized to the endocytic compartments and a similar apical distribution in the proximal tubules was demonstrated after intravenous injection of 125I-TC-B12. The TC-B12 binding sites in the proximal tubule epithelium colocalized with megalin as shown by ligand binding to cryosections of rat kidney cortex, and the binding was inhibited by anti-megalin polyclonal antibody, EDTA, and RAP. These data show a novel nutritional dimension of megalin as a receptor involved in the cellular uptake of vitamin B12. The expression of megalin in absorptive epithelia in the kidney and other tissues including yolk sac and placenta suggests a role of the receptor in vitamin B12 homeostasis and fetal vitamin B12 supply.
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Cited by
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TUMA, P. L., & HUBBARD, A. L. (2003) · Physiological Reviews · doi:10.1152/physrev.00001.2003 · Cited by 681
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Vitamin B12 transport from food to the body's cells—a sophisticated, multistep pathway
Nielsen, M. J., Rasmussen, M. R., Andersen, C. B. F., Nexø, E., & Moestrup, S. K. (2012) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2012.76 · Cited by 403
Self-citationVitamin B12 among Vegetarians: Status, Assessment and Supplementation
Rizzo, G., Laganà, A., Rapisarda, A., La Ferrera, G., Buscema, M., Rossetti, P., Nigro, A., Muscia, V., Valenti, G., Sapia, F., et al. (2016) · Nutrients · doi:10.3390/nu8120767 · Cited by 372
Kozyraki, R., Fyfe, J., Kristiansen, M., Gerdes, C., Jacobsen, C., Cui, S., Christensen, E. I., Aminoff, M., de la Chapelle, A., Krahe, R., et al. (1999) · Nature Medicine · doi:10.1038/9504 · Cited by 273
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Metadata
- Authors
- Moestrup, S. K., Birn, H., Fischer, P. B., Petersen, C. M., Verroust, P. J., Sim, R. B., Christensen, E. I., & Nexø, E.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 1996-08-06
- Volume
- 93
- Issue
- 16
- Pages
- 8612-8617
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2018710099
- Cited by
- 216
- References
- 0
- FWCI
- 9.45
- Type
- journal article
- Language
- en
- Open access
- green
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- Moestrup, S. K., Birn, H., Fischer, P. B., Petersen, C. M., Verroust, P. J., Sim, R. B., Christensen, E. I., & Nexø, E. (1996). Megalin-mediated endocytosis of transcobalamin-vitamin-B12 complexes suggests a role of the receptor in vitamin-B12 homeostasis. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.93.16.8612
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