Cationic amino acid transport across the blood-brain barrier is mediated exclusively by system y⁺

Abstract

Cationic amino acid (CAA) transport is brought about by two families of proteins that are found in various tissues: Cat (CAA transporter), referred to as system y+, and Bat [broad-scope amino acid (AA) transporter], which comprises systems b0,+, B0,+, and y+L. CAA traverse the blood-brain barrier (BBB), but experiments done in vivo have only been able to examine the BBB from the luminal (blood-facing) side. In the present study, plasma membranes isolated from bovine brain microvessels were used to identify and characterize the CAA transporter(s) on both sides of the BBB. From these studies, it was concluded that system y+ was the only transporter present, with a prevalence of activity on the abluminal membrane. System y+ was voltage dependent and had a Km of 470 +/- 106 microM (SE) for lysine, a Ki of 34 microM for arginine, and a Ki of 290 microM for ornithine. In the presence of Na+, system y+ was inhibited by several essential neutral AAs. The Ki values were 3-10 times the plasma concentrations, suggesting that system y+ was not as important a point of access for these AAs as system L1. Several small nonessential AAs (serine, glutamine, alanine,and glycine) inhibited system y+ with Ki values similar to their plasma concentrations, suggesting that system y+ may account for the permeability of the BBB to these AAs. System y+ may be important in the provision of arginine for NO synthesis. Real-time PCR and Western blotting techniques established the presence of the three known nitric oxide synthases in cerebral endothelial cells: NOS-1 (neuronal), NOS-2 (inducible), and NOS-3 (endothelial). These results confirm that system y+ is the only CAA transporter in the BBB and suggest that NO can be produced in brain endothelial cells.

Cationic amino acid transporter 1‐mediated l‐arginine transport at the inner blood–retinal barrier

“…The source of L-arginine in humans and most mammals is mostly renal de novo synthesis and dietary intake, and that of L-lysine, an essential amino acid, is exclusively by dietary intake, showing that L-arginine and L-lysine must be taken up by the retina from the circulating blood. CAT1 is reported to mediate the transport of cationic amino acids at the blood-brain barrier (Stoll et al 1993;O'Kane et al 2006), implying the similar roles of CAT1 in neural tissues. Accordingly, CAT1 in neural tissues such as retina and brain is physiologically essential for satisfying the neural requirements of L-arginine and L-lysine through its functional expression at the barrier-forming cells.…”

Establishment of a new conditionally immortalized human brain microvascular endothelial cell line retaining an in vivo blood–brain barrier function

“…4A). System y þ exists at the BBB and works as a Na þ -independent basic amino acid transport system which transports L-Lys and L-Arg (O'Kane et al, 2006). The cationic acid transporter 1 (CAT-1), which is responsible for system y þ activity, was also expressed in the TY08 cells (Fig.…”

Comparison of the Effects of Ornithine and Arginine on the Brain Protein Synthesis Rate in Young Rats

“…On the other hand, in the present study, the concentration of plasma GH also rose after arginine ingestion. However, several studies supported the possibility that arginine itself passed the blood-brain barrier (22). Therefore, the role of dietary arginine in brain protein synthesis in hypophysectomized rats is another question to consider in further study in order to investigate whether the changes in brain protein synthesis with arginine treatment are mediated through the concentration of GH.…”