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

¹Natural and Applied Science Department, LaGuardia Community College/City University of New York, Long Island City, New York; ²Departamento de Bioquímica & Biología Molecular, Facultad de Medicina, Universitat de Valencia, Valencia, Spain; ³Department of Neural and Behavioral Sciences, Milton S. Hershey Medical Center, Penn State University College of Medicine, Hershey, Pennsylvania; and ⁴Department of Physiology & Biophysics, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois

Submitted 5 January 2006 ; accepted in final form 24 March 2006

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 b^0,+, B^0,+, 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 K_m of 470 ± 106 µM (SE) for lysine, a K_i of 34 µM for arginine, and a K_i of 290 µM for ornithine. In the presence of Na⁺, system y⁺ was inhibited by several essential neutral AAs. The K_i 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 K_i 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.

amino acid active transport; brain capillaries; endothelial cells; essential amino acids; nonessential amino acids; polarity