ATA2 Is Predominantly Expressed as System A at the Blood-Brain Barrier and Acts as Brain-to-Blood Efflux Transport forl-Proline

• Published in: Molecular pharmacology Vol. 61; no. 6; pp. 1289 - 1296
• Main Authors: Takanaga, Hitomi, Tokuda, Noriyo, Ohtsuki, Sumio, Hosoya, Ken-ichi, Terasaki, Tetsuya
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.06.2002
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.61.6.1289

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 α-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 μM) 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.