Predominant functional activity of the large, neutral amino acid transporter (LAT1) isoform at the cerebrovasculature.
In this study, we identify the predominant functional expression of the large, neutral amino acid transporter (LAT1) isoform at the blood-brain barrier (BBB). An in situ rat brain perfusion technique allowed perfusion of the radiotracer [(14)C]-L-Leu (a ligand for both LAT1 and LAT2) alone or competed with excess concentration of either LAT1 or LAT2 specific amino acids. The LAT2 specific amino acid, [(14)C]-L-Asn, was perfused alone or with excess concentration of various amino acids. The brain uptake of [(14)C]-L-Leu was not significantly inhibited by LAT2 specific amino acids, but was inhibited significantly (up to 90%) by the LAT1 specific amino acid, D-Met. L-Asn did not demonstrate saturable brain uptake. These data clearly demonstrate that LAT1 is the functionally predominant isoform expressed at the BBB which is responsible for brain uptake of large, neutral amino acids. In addition, the functional activity of cerebrovascular LAT2 is insignificant, or absent.
Killian
D M
DM
Department of Pharmaceutical Sciences, 20 North Pine Street, University of Maryland, Baltimore, MD 21201, USA.
Chikhale
P J
PJ
D026905:Amino Acid Transport Systems; D000596:Amino Acids / Q000493:pharmacokinetics; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D002536:Cerebral Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium / Q000493:pharmacokinetics
D026905:Amino Acid Transport Systems; D000596:Amino Acids; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D020033:Protein Isoforms; D014316:Tritium