Molecular and functional identification of large neutral amino acid transporters LAT1 and LAT2 and their pharmacological relevance at the blood-brain barrier

2001 ◽  
Vol 53 (4) ◽  
pp. 497-503 ◽  
Author(s):  
Yasuto Kido ◽  
Ikumi Tamai ◽  
Hiroshi Uchino ◽  
Fumio Suzuki ◽  
Yoshimichi Sai ◽  
...  
Keyword(s):  
Amino Acid ◽  
Blood Brain Barrier ◽  
Neutral Amino Acid ◽  
Brain Barrier ◽  
Amino Acid Transporters ◽  
Large Neutral Amino Acid ◽  
Functional Identification ◽  
Blood Brain

Na+-dependent neutral amino acid transporters A, ASC, and N of the blood-brain barrier: mechanisms for neutral amino acid removal

2004 ◽  
Vol 287 (4) ◽  
pp. E622-E629 ◽  
Author(s):  
Robyn L. O'Kane ◽  
Juan R. Viña ◽  
Ian Simpson ◽  
Richard A. Hawkins
Keyword(s):  
Amino Acid ◽  
Blood Brain Barrier ◽  
Functional Organization ◽  
Extracellular Fluid ◽  
Neutral Amino Acid ◽  
Brain Barrier ◽  
Amino Acid Transporters ◽  
System A ◽  
Blood Brain ◽  
Voltage Dependent

Four Na+-dependent transporters of neutral amino acids (NAA) are known to exist in the abluminal membranes (brain side) of the blood-brain barrier (BBB). This article describes the kinetic characteristics of systems A, ASC, and N that, together with the recently described Na+-dependent system for large NAA (Na+-LNAA), provide a basis for understanding the functional organization of the BBB. The data demonstrate that system A is voltage dependent (3 positive charges accompany each molecule of substrate). Systems ASC and N are not voltage dependent. Each NAA is a putative substrate for at least one system, and several NAA are transported by as many as three. System A transports Pro, Ala, His, Asn, Ser, and Gln; system ASC transports Ser, Gly, Met, Val, Leu, Ile, Cys, and Thr; system N transports Gln, His, Ser, and Asn; Na+-LNAA transports Leu, Ile, Val, Trp, Tyr, Phe, Met, Ala, His, Thr, and Gly. Together, these four systems have the capability to actively transfer every naturally occurring NAA from the extracellular fluid (ECF) to endothelial cells and thence to the circulation. The existence of facilitative transport for NAA (L1) on both membranes provides the brain access to essential NAA. The presence of Na+-dependent carriers on the abluminal membrane provides a mechanism by which NAA concentrations in the ECF of brain are maintained at ∼10% of those of the plasma.

scholarly journals Role of Oxoproline in the Regulation of Neutral Amino Acid Transport across the Blood-Brain Barrier

1996 ◽  
Vol 271 (32) ◽  
pp. 19129-19133 ◽  
Author(s):  
Wha-Joon Lee ◽  
Richard A. Hawkins ◽  
Darryl R. Peterson ◽  
Juan R. Viña
Keyword(s):  
Amino Acid ◽  
Blood Brain Barrier ◽  
Amino Acid Transport ◽  
Neutral Amino Acid ◽  
Brain Barrier ◽  
Acid Transport ◽  
Blood Brain

scholarly journals Carrier-Mediated Delivery of Metabotropic Glutamate Receptor Ligands to the Central Nervous System: Structural Tolerance and Potential of the l-system Amino Acid Transporter at the Blood-Brain Barrier

2000 ◽  
Vol 20 (1) ◽  
pp. 168-174 ◽  
Author(s):  
Andreas Reichel ◽  
David J. Begley ◽  
N. Joan Abbott
Keyword(s):  
Central Nervous System ◽  
Amino Acid ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Side Chain ◽  
Large Neutral Amino Acid ◽  
Metabotropic Glutamate ◽  
Blood Brain ◽  
L System ◽  
The Brain

The brain endothelial large neutral amino acid carrier (l-system) is well suited for facilitated drug transport to the brain because of its high transport capacity and relatively broad structural substrate tolerance. The authors have examined the potential of this transporter for central nervous system (CNS) delivery of a new family of compounds derived from the large neutral amino acid phenylglycine. These compounds are highly selective for specific isoforms of metabotropic glutamate receptors (mGluRs) but will only become effective therapeutics for CNS diseases such as ischemic disorders, stroke, and epilepsy if they can effectively cross the blood-brain barrier. Using the immortalized rat brain endothelial cell line RBE4 as in vitro blood-brain barrier model, the authors have studied the interaction of phenylglycine and selected derivatives with the l-system-mediated transport of l-[3H]-histidine. The transport of l-histidine was characteristic of the l-system in vivo with the following kinetic parameters: Km 135 ± 18 μmol/L, Vmax 15.3 ± 1.13 nmol/min/mg protein, and KD 2.38 ± 0.84 μL/min/mg protein. The affinities of the l-system for phenylglycine and the derivatives investigated increased in the order S-4-carboxy-phenylglycine (Ki = 16 mmol/L) < R-phenylglycine (2.2 mmol/L) < S-3-hydroxy-phenylglycine (48 μmol/L) < S-phenylglycine (34 μmol/L), suggesting that a negative charge at the side chain or R-configuration is detrimental for carrier recognition, whereas neutral side chain substituents are well tolerated. The authors have further shown (1) that the mode of interaction with the l-system of S-phenylglycine and S-3-hydroxy-phenylglycine is competitive, and (2) that the transporter carries these two agents into the cell as shown by high-performance liquid chromatography (HPLC) analysis of the RBE4 cell contents. The study provides the first evidence for the potential of S-phenylglycine derivatives for carrier-mediated delivery to the CNS and outlines the substrate specificity of the l-system at the blood-brain barrier for this class of mGluR ligands. As the affinities of S-phenylglycine and S-3-hydroxy-phenylglycine for the l-system carrier are even higher than those of some natural substrates, these agents should efficiently enter CNS via this route. Possible strategies for a synergistic optimization of phenylglycine-derived therapeutics with respect to desired activity at the CNS target combined with carrier-mediated delivery to overcome the blood-brain barrier are discussed.

Expression of a system L neutral amino acid transporter at the blood–brain barrier

Neuroreport ◽  
2000 ◽  
Vol 11 (16) ◽  
pp. 3507-3511 ◽  
Author(s):  
Hirotaka Matsuo ◽  
Shingo Tsukada ◽  
Takahiro Nakata ◽  
Arthit Chairoungdua ◽  
Do Kyung Kim ◽  
...  
Keyword(s):  
Amino Acid ◽  
Blood Brain Barrier ◽  
Amino Acid Transporter ◽  
Neutral Amino Acid ◽  
Brain Barrier ◽  
Neutral Amino Acid Transporter ◽  
Blood Brain ◽  
System L ◽  
Acid Transporter
Sign in / Sign up

Export Citation Format

Share Document