ATA2 is predominantly expressed as system A at the blood-brain barrier and acts as brain-to-blood efflux transport for L-proline

Although system A is present at the blood-brain barrier (BBB), the physiological roles of system A have not been clarified. The efflux transport of the substrates of system A, such as L-proline (L-Pro), glycine (Gly), and alpha-methylaminoisobutyric acid (MeAIB), across the BBB was investigated usin...

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Bibliographic Details
Published in:Molecular pharmacology 2002-06, Vol.61 (6), p.1289-1296
Main Authors: Takanaga, Hitomi, Tokuda, Noriyo, Ohtsuki, Sumio, Hosoya, Ken-Ichi, Terasaki, Tetsuya
Format: Article
Language:English
Subjects:
Amino Acid Transport System A - biosynthesis
Amino Acid Transport System A - genetics
Amino Acid Transport System A - metabolism
Amino Acids - pharmacology
Animals
beta-Alanine - analogs & derivatives
beta-Alanine - metabolism
Biological Transport
Blood-Brain Barrier - physiology
Brain - metabolism
Dose-Response Relationship, Drug
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Glycine - metabolism
Hypertonic Solutions - pharmacology
Male
Proline - metabolism
Rats
Rats, Wistar
RNA, Messenger - metabolism
Sodium - metabolism
Time Factors
Tritium
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Summary:Although system A is present at the blood-brain barrier (BBB), the physiological roles of system A have not been clarified. The efflux transport of the substrates of system A, such as L-proline (L-Pro), glycine (Gly), and alpha-methylaminoisobutyric acid (MeAIB), across the BBB was investigated using the in vivo Brain Efflux Index method. Over a period of 40 min, L-[(3)H]Pro and [(3)H]Gly underwent efflux from the brain, whereas [(3)H]MeAIB did not. The efflux of L-[(3)H]Pro was inhibited by the presence of unlabeled L-Pro and MeAIB, suggesting that carrier-mediated efflux transport of L-Pro across the BBB is involved in system A. L-[(3)H]Pro uptake by TR-BBB cells, used as an in vitro BBB model, was Na(+)-dependent with high-affinity (K(m1) = 425 microM) and low-affinity (K(m2) = 10.8 mM) saturable processes. The manner of inhibition of L-[(3)H]Pro uptake for amino acids was consistent with system A. Although GlnT, ATA2, and ATA3 mRNA were all expressed in TR-BBB cells, ATA2 mRNA was predominant. Under hypertonic conditions, ATA2 mRNA in TR-BBB cells was induced by up to 373%, and it activated [(3)H]MeAIB uptake. In light of these observations, our results indicate that L-Pro and Gly are transported from the brain across the BBB, whereas MeAIB is retained in the brain. System A is involved in efflux transport for L-Pro at the BBB. The predominantly expressed ATA2 mRNA at the BBB may play a role in maintaining the concentration of small neutral amino acids and cerebral osmotic pressure in the brain under pathological conditions.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.61.6.1289