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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Role of PEPT2 in Peptide/Mimetic Trafficking at the Blood-Cerebrospinal Fluid Barrier: Studies in Rat Choroid Plexus Epithelial Cells in Primary Culture

Cathaleen Shu, Hong Shen, Nathan S. Teuscher, Philip J. Lorenzi, Richard F. Keep and David E. Smith
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 820-829; DOI: https://doi.org/10.1124/jpet.301.3.820
Cathaleen Shu
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Hong Shen
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Nathan S. Teuscher
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Philip J. Lorenzi
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Richard F. Keep
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David E. Smith
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Abstract

Recent studies have established the functional and molecular presence of a high-affinity peptide transporter, PEPT2, in whole tissue rat choroid plexus. However, the precise membrane location and directionality of PEPT2-mediated transport is uncertain at present. In this study, we examined the transport kinetics of a model dipeptide, glycylsarcosine (GlySar), along with the protein expression of PEPT2 using primary cell cultures of choroidal epithelium from neonatal rats. GlySar accumulation and transepithelial transport were 3 to 4 times higher when introduced from the apical as opposed to the basal side of the monolayers. GlySar apical uptake was also stimulated by an inwardly directed proton gradient. The uptake of GlySar was inhibited by di/tripeptides, carnosine, and α-amino cephalosporins but was unaffected by amino acids, cephalosporins lacking an α-amino group, and organic anions and cations. The Michaelis constant (Km) of GlySar was 59.6 μM for apical uptake and 1.4 mM for basal uptake; this is consistent with the high-affinity properties of PEPT2 at the apical membrane. Immunoblot analyses and immunofluorescent confocal microscopy demonstrated the presence of PEPT2, but not PEPT1, in rat choroid plexus epithelial cells. Moreover, PEPT2 was present in the apical and subapical regions of the cell but was absent in the basolateral membrane. These findings demonstrate, for the first time, that PEPT2 protein is present at the apical membrane of choroidal epithelial cells and that it is functionally active at this membrane surface. The results suggest that PEPT2 may have a role in the efflux of peptides and/or mimetics from cerebrospinal fluid to the blood.

Footnotes

  • This work was supported in part by Grants R01 GM035498 (to D.E.S.), R01 NS034709 and P01 HL018575 (to R.F.K.), P60 DK020572 (Michigan Diabetes Research and Training Center Core) from the National Institutes of Health, and by the Vahlteich Research Award from the University of Michigan College of Pharmacy. N.S.T. was supported by an American Foundation for Pharmaceutical Education Fellowship, a Rackham Predoctoral Fellowship, and the Pharmacological Sciences Training Program of the National Institutes of Health (Grant T32 GM007767).

  • Abbreviations:
    CSF
    cerebrospinal fluid
    GlySar
    glycylsarcosine
    TEER
    transepithelial electrical resistance
    MES
    2-(N-morpholino)ethanesulfonic acid
    HPLC
    high-performance liquid chromatography
    CNS
    central nervous system
    TPP
    tripeptidyl-peptidases
    SITS
    4-acetamido-4′-isothiocyanatostilbene-2,2′-disulfonic acid
    PAH
    p-aminohippuric acid
    NMN
    N1-methylnicotinamide
    • Received December 6, 2001.
    • Accepted February 20, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Role of PEPT2 in Peptide/Mimetic Trafficking at the Blood-Cerebrospinal Fluid Barrier: Studies in Rat Choroid Plexus Epithelial Cells in Primary Culture

Cathaleen Shu, Hong Shen, Nathan S. Teuscher, Philip J. Lorenzi, Richard F. Keep and David E. Smith
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 820-829; DOI: https://doi.org/10.1124/jpet.301.3.820

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Role of PEPT2 in Peptide/Mimetic Trafficking at the Blood-Cerebrospinal Fluid Barrier: Studies in Rat Choroid Plexus Epithelial Cells in Primary Culture

Cathaleen Shu, Hong Shen, Nathan S. Teuscher, Philip J. Lorenzi, Richard F. Keep and David E. Smith
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 820-829; DOI: https://doi.org/10.1124/jpet.301.3.820
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