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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 6, 2006; DOI: 10.1124/jpet.105.096149

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Received for publication September 26, 2005.
Revised January 5, 2006.
Accepted for publication January 5, 2006.

RECOGNITION, CO-INTERNALIZATION AND RECYCLING OF AN AVIAN RIBOFLAVIN CARRIER PROTEIN IN HUMAN PLACENTAL TROPHOBLASTS

Clifford W Mason 1, Vanessa M D'Souza 1, Lisa M Bareford 1, Mitch A Phelps 2, Abhijit Ray 1, Peter W. Swaan 1*

1 University of Maryland 2 The Ohio State University

* Address correspondence to: E-mail: pswaan{at}rx.umaryland.edu

Abstract

Absorption of riboflavin (RF) across membrane barriers is essential to cellular oxidationreduction processes. Riboflavin carrier protein (RCP), a 37 kDa secretory protein, is proposed to play an important role in RF absorption, although information on the mammalian ortholog remains unclear. This study alludes to the existence of a mammalian RF carrier protein and further characterizes its carrier role and fate using avian RCP in human placental trophoblast (BeWo), another mammalian cell line, monkey kidney (COS- 1), and the avian control, chicken hepatic (LMH/2A) cells. The presence of RCP and its involvement in RF internalization was analyzed by immunofluorescence and immuno-binding assays using chicken RCP (cRCP) antibodies. In the presence of anti-cRCP, cellular RF uptake is significantly decreased (5% of control) in BeWo cells. Kinetic analyses of intracellular accumulation of [125I]-cRCP revealed a Jmax and Km of 28.56 ± 2.70 pmol/mg protein/min and 142.43 ± 82.16 nM, respectively, in BeWo cells and 75.14 ± 7.6 pmol/mg protein/min and 104.37 ± 23.96 nM in the species specific control, LMH/2A cells. Subcellular fractionation studies revealed colocalization of both radiolabeled RF and cRCP within endosomal and lysosomal fractions, further elucidating RCP's role in trafficking RF through the cell. Following intracellular release of RF from the carrier complex, the protein is either subject to lysosomal breakdown or is conserved via recycling mechanisms for continued RF sequestration and uptake. In summary, mammalian placental trophoblasts, exhibit specific carrier protein dependence that sequesters and essentially mediates RF internalization via the proposed receptor-mediated endocytic pathway.


Key words: carrier protein, endocytosis, placenta, riboflavin, transport, trophoblast


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A. B. Foraker, A. Ray, T. C. Da Silva, L. M. Bareford, K. M. Hillgren, T. D. Schmittgen, and P. W. Swaan
Dynamin 2 Regulates Riboflavin Endocytosis in Human Placental Trophoblasts
Mol. Pharmacol., September 1, 2007; 72(3): 553 - 562.
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