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Synergism between the Two Membranes of the Blood-brain Barrier: Glucose and Amino Acid Transport

Richard Albert Hawkins, Juan R. Viña, A. Mokashi, Darryl R. Peterson, R. O’Kane, Ian A. Simpson, Mary Regina Dejoseph, Hector Rasgado-Flores

Abstract


Brain capillary endothelial cells, which are connected by extensive tight junctions and are polarized into luminal (blood-facing) and abluminal (brain-facing) plasma membrane domains, form the blood-brain barrier (BBB). The polar distribution of transport proteins mediates glucose and amino acid (AA) homeostasis in the brain. The ability to isolate the luminal and abluminal membranes has permitted the study of each side of the BBB separately in vitro and yielded new information on BBB function. The two membranes have different characteristics. Facilitative transporters were found on both membranes in a position to permit the bidirectional transport of glucose, almost all amino acids and taurine. Na+-dependent transporters were only found on abluminal membranes. The Na+-dependent transporters on the abluminal side are capable of removing virtually all amino acids including acidic AA from the extracellular fluid of brain (ECF). The presence of Na+-dependent carriers on the abluminal membrane provides a mechanism by which the concentrations of AA, glucose and taurine in the ECF of brain may be maintained at optimal levels under physiological and pathophysiological circumstances. Facilitative carriers for glutamine (n) and glutamate (xg-) are found only in the luminal membrane of the BBB. This organization allows the net removal of acidic and nitrogen-rich AA from brain, and explains the low rate of glutamate and glutamine penetration into the central nervous system. The presence of a g-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 g-glutamyl cycle is expected to generate pyroglutamate within the endothelial cells. Pyroglutamate stimulates Na+-dependent AA transporters at the abluminal membrane thereby reducing net influx of AA the to brain. It is now clear the BBB may actively participate in the regulation of the AA content of the brain as well as contributing to the control of brain osmolarity.


Keywords


Facilitative transport; Na+-dependent transport; Neutral amino acids; Acidic amino acids; Taurine; Glucose; Membranes; Pyroglutamate; Osmolytes

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