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J. Biol. Chem., Vol. 278, Issue 7, 4786-4791, February 14, 2003
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From the The presence of multiple oligopeptide
transporters in brain has generated considerable interest as to their
physiological role in neuropeptide homeostasis, pharmacologic
importance, and potential as a target for drug delivery through the
blood-brain and blood-cerebrospinal fluid barriers. To understand
further the purpose of specific peptide transporters in brain, we have generated PEPT2-deficient mice by targeted gene disruption.
Homozygous PepT2 null mice lacked expression of PEPT2
mRNA and protein in choroid plexus and kidney, tissues in which
PepT2 is normally expressed, whereas heterozygous mice displayed PepT2
expression levels that were intermediate between those of wild-type and
homozygous null animals. Mutant PepT2 null mice were found to be
viable, grew to normal size and weight, and were without obvious kidney or brain abnormalities. Notwithstanding the lack of apparent biological effects, the proton-stimulated uptake of 1.9 µM
glycylsarcosine (a model, hydrolysis-resistant dipeptide) in isolated
choroid plexus was essentially ablated (i.e. residual
activity of 10.9 and 3.9% at 5 and 30 min, respectively). These novel
findings provide strong evidence that, under the experimental
conditions of this study, PEPT2 is the primary member of
the peptide transporter family responsible for dipeptide uptake in
choroid plexus tissue.
Targeted Disruption of the PEPT2 Gene Markedly
Reduces Dipeptide Uptake in Choroid Plexus*
,§,
,**
Department of Pharmaceutical Sciences,
College of Pharmacy, Departments of ¶ Neurosurgery,
Physiology, and ** Internal Medicine, the
University of Michigan, Ann Arbor, Michigan 48109
*
This work was supported in part by Grants R01 GM035498 (to
D. E. S.), R01 NS034709, and P01 HL018575 (to R. F. K.) from the National Institutes of Health and by an Upjohn Research Award from the
University of Michigan College of Pharmacy.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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