Amino Acid Transport Across Each Side Of The Blood-Brain Barrier

Brain capillary endothelial cells form the blood-brain barrier (BBB). They are connected by extensive tight junctions, and are polarized into luminal (blood-facing) and abluminal (brain-facing) plasma membrane domains. The polar distribution of transport proteins mediates amino acid (AA) homeostasis in the brain. The existence of two facilitative transporters for neutral amino acids (NAA) on both membranes provides the brain access to essential AA. Four Na+-dependent transporters of NAA exist in the abluminal membranes of the BBB. Together these 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 presence of Na+-dependent carriers on the abluminal membrane provides a mechanism by which NAA concentrations in the ECF of brain are maintained at about 10% of those of the plasma. Also present on the abluminal membrane are at least three Na+-dependent systems transporting acidic AA (EAAT) and a Na+-dependent system transporting glutamine (N). Facilitative carriers for glutamine and glutamate are found only in the luminal membrane of the BBB. This organization promotes the net removal of acidic and nitrogen-rich AA from brain, and accounts for the low level of glutamate penetration into the central nervous system (CNS). The presence of a gamma-glutamyl cycle at the luminal membrane and Na+-dependent AA transporters at the abluminal membrane may serve to modulate movement of AA from blood to brain. The gamma-glutamyl cycle is expected to generate pyroglutamate within the endothelial cells. Pyroglutamate stimulates secondary active AA transporters at the abluminal membrane, thereby reducing net influx of AA to the brain. It is now clear the BBB participates in the active regulation of the AA content of the brain.