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

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.