Document Detail


The proton-coupled amino acid transporter, SLC36A1 (hPAT1), transports Gly-Gly, Gly-Sar and other Gly-Gly mimetics.
MedLine Citation:
PMID:  20880398     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
S Frølund; R Holm; B Brodin; C U Nielsen
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  British journal of pharmacology     Volume:  161     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-30     Completed Date:  2011-01-24     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  589-600     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark.
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MeSH Terms
Descriptor/Qualifier:
5-Hydroxytryptophan / 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:
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
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