The l-isomer-selective transport of aspartic acid is mediated by ASCT2 at the blood-brain barrier.
Aspartic acid (Asp) undergoes l-isomer-selective efflux transport across the blood-brain barrier (BBB). This transport system appears to play an important role in regulating l- and d-Asp levels in the brain. The purpose of this study was to identify the responsible transporters and elucidate the mechanism for l-isomer-selective Asp transport at the BBB. The l-isomer-selective uptake of Asp by conditionally immortalized mouse brain capillary endothelial cells used as an in vitro model of the BBB took place in an Na+- and pH-dependent manner. This process was inhibited by system ASC substrates such as l-alanine and l-serine, suggesting that system ASC transporters, ASCT1 and ASCT2, are involved in the l-isomer selective transport. Indeed, l-Asp uptake by oocytes injected with either ASCT1 or ASCT2 cRNA took place in a similar manner to that in cultured BBB cells, whereas no significant d-Asp uptake occurred. Although both ASCT1 and ASCT2 mRNA were expressed in the cultured BBB cells, the expression of ASCT2 mRNA was 6.7-fold greater than that of ASCT1. Moreover, immunohistochemical analysis suggests that ASCT2 is localized at the abluminal side of the mouse BBB. These results suggest that ASCT2 plays a key role in l-isomer-selective Asp efflux transport at the BBB.
Tetsuka
Kazuhiro
K
Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences New Industry Creation Hatchery Center, Tohoku University, Sendai, Japan. terasaki@mail.pharm.tohoku.ac.jp
Takanaga
Hitomi
H
Ohtsuki
Sumio
S
Hosoya
Ken-ichi
K
Terasaki
Tetsuya
T
D026962:Amino Acid Transport System ASC / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism* / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000166:cytology; D002196:Capillaries / Q000166:cytology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D007536:Isomerism; D051379:Mice; D015778:Minor Histocompatibility Antigens; D009865:Oocytes / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D013379:Substrate Specificity / Q000502:physiology; D014981:Xenopus
D026962:Amino Acid Transport System ASC; D000596:Amino Acids; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; C498847:Slc1a4 protein, mouse; C420504:Slc1a4 protein, rat; C498850:Slc1a5 protein, mouse; C498849:Slc1a5 protein, rat; D001224:Aspartic Acid; D012964:Sodium