| The proton-coupled amino acid transporter, SLC36A1 (hPAT1), transports Gly-Gly, Gly-Sar and other Gly-Gly mimetics. | |
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MedLine Citation:
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PMID: 20880398 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE The intestinal proton-coupled amino acid transporter, SLC36A1, transports zwitterionic α-amino acids and drugs such as vigabatrin, gaboxadol and δ-aminolevulinic acid. We hypothesize that SLC36A1 might also transport some dipeptides. The aim of the present study was to investigate SLC36A1-mediated transport of Gly-Gly and Gly-Gly mimetics, and to investigate Gly-Sar transport via SLC36A1 and the proton-coupled dipeptide/tripeptide transporter, SLC15A1 in Caco-2 cells. EXPERIMENTAL APPROACH Transport of a compound via SLC36A1 was determined by its ability to induce an increase in the inward current of two-electrode voltage clamped SLC36A1 cRNA-injected Xenopus laevis oocytes. SLC36A1-mediated L-[³H]Pro uptake in Caco-2 cells was measured in the absence and presence of Gly-Gly or Gly-Sar. In addition, apical [¹⁴C]Gly-Sar uptake was measured in the absence and presence of the SLC36A1 inhibitor 5-hydroxy-L-tryptophan (5-HTP) or the SLC15A1 inhibitor L-4,4'-biphenylalanyl-L-proline (Bip-Pro). KEY RESULTS In SLC36A1-expressing oocytes, an inward current was induced by Gly-Sar, Gly-Gly, δ-aminolevulinic acid, β-aminoethylglycine, δ-aminopentanoic acid, GABA, Gly and Pro, whereas Val, Leu, mannitol, 5-HTP and the dipeptides Gly-Ala, Gly-Pro and Gly-Phe did not evoke currents. In Caco-2 cell monolayers, the apical uptake of 30 mM Gly-Sar was inhibited by 20 and 22% in the presence of 5-HTP or Bip-Pro, respectively, and by 48% in the presence of both. CONCLUSION AND IMPLICATIONS Our results suggest that whereas Gly-Gly amid bond bioisosteres are widely accepted by the hPAT1 carrier, dipeptides in general are not; and therefore, Gly-Sar might structurally define the size limit of dipeptide transport via SLC36A1. |
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Authors:
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S Frølund; R Holm; B Brodin; C U Nielsen |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: British journal of pharmacology Volume: 161 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-30 Completed Date: 2011-01-24 Revised Date: 2012-05-07 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 589-600 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark. |
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| MeSH Terms | |
Descriptor/Qualifier:
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5-Hydroxytryptophan
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pharmacology Amino Acid Transport Systems / antagonists & inhibitors, metabolism* Animals Biological Transport / drug effects* Caco-2 Cells Dipeptides / metabolism* Glycylglycine / analogs & derivatives*, metabolism* Humans Intestinal Absorption / drug effects Oocytes / metabolism Patch-Clamp Techniques / methods Symporters / antagonists & inhibitors, metabolism* Xenopus laevis |
| Chemical | |
Reg. No./Substance:
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0/Amino Acid Transport Systems; 0/Dipeptides; 0/SLC36A1 protein, human; 0/Symporters; 29816-01-1/glycylsarcosine; 556-50-3/Glycylglycine; 56-69-9/5-Hydroxytryptophan |
| Comments/Corrections | |
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