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Molecular Pharmacology Fast Forward
First published on June 12, 2007; DOI: 10.1124/mol.107.037101

0026-895X/07/7203-553-562$20.00
Mol Pharmacol 72:553-562, 2007

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Dynamin 2 Regulates Riboflavin Endocytosis in Human Placental Trophoblasts

Amy B. Foraker, Abhijit Ray, Tatiana Claro Da Silva, Lisa M. Bareford, Kathleen M. Hillgren, Thomas D. Schmittgen, and Peter W. Swaan

Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland (A.B.F., A.R., T.C.D.S., L.M.B., P.W.S.); Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.M.H.); and Division of Pharmaceutics, College of Pharmacy, the Ohio State University, Columbus, Ohio (T.D.S.)

Riboflavin is thoroughly established to be indispensable in a multitude of cellular oxidation-reduction reactions through its conversion to coenzyme forms flavin mononucleotide and flavin adenine dinucleotide. Despite its physiological importance, little is known about specific mechanisms or proteins involved in regulating its cellular entry in humans. Studies involving biochemical modulators and immunological inhibition assays have indirectly revealed that riboflavin internalization and trafficking occurs at least in part through a clathrin-dependent receptor-mediated endocytic process. Here, using a two-tiered strategy involving RNA interference and the overexpression of dominant-negative constructs, we directly show the involvement of this endocytic mechanism through the requirement of the pluripotent endocytic vesicle scission enzyme, dynamin 2 GTPase, in human placental trophoblasts. Similar to the endocytic control ligand, transferrin, riboflavin is shown to exhibit 50% dependence on the functional expression of dynamin 2 for its active cellular entry. Furthermore, this reduced vitamin uptake correlates with >2-fold higher riboflavin association at the cell surface. In addition, fluorescent ligand endocytosis assays showing colocalization between rhodamine-riboflavin and the immunostained caveolar coat protein, caveolin 1, suggest that the active absorption of this important nutrient involves multiple and distinct endocytosis pathways.

Received for publication April 13, 2007.

Accepted for publication June 12, 2007.

Address correspondence to: Dr. Peter W. Swaan, Department of Pharmaceutical Sciences, University of Maryland, 20 Penn Street, HSF2–621, Baltimore, MD 21201. E-mail: pswaan{at}rx.umaryland.edu






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