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This Article Full Text Full Text (PDF) All Versions of this Article: 90/3/867S    most recent ajcn.2009.27462BBv1 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Hawkins, R. A PubMed PubMed Citation Articles by Hawkins, R. A Agricola Articles by Hawkins, R. A

The blood-brain barrier and glutamate^1,2,3,4

¹ From the Department of Physiology and Biophysics, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL.

² Presented at the "100th Anniversary Symposium of Umami Discovery: The Roles of Glutamate in Taste, Gastrointestinal Function, Metabolism, and Physiology," held in Tokyo, Japan, 10–13 September 2008.

³ Supported by the National Institutes of Health (grant nos. NS31017 and NS041405) and by the International Glutamate Technical Committee, a nongovernmental organization funded by industrial producers and users of glutamate in food.

⁴ Address correspondence to RA Hawkins, Department of Physiology and Biophysics, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064-3095. E-mail: rah{at}post.harvard.edu.

Glutamate concentrations in plasma are 50–100 µmol/L; in whole brain, they are 10,000–12,000 µmol/L but only 0.5–2 µmol/L in extracellular fluids (ECFs). The low ECF concentrations, which are essential for optimal brain function, are maintained by neurons, astrocytes, and the blood-brain barrier (BBB). Cerebral capillary endothelial cells form the BBB that surrounds the entire central nervous system. Tight junctions connect endothelial cells and separate the BBB into luminal and abluminal domains. Molecules entering or leaving the brain thus must pass 2 membranes, and each membrane has distinct properties. Facilitative carriers exist only in luminal membranes, and Na⁺-dependent glutamate cotransporters (excitatory amino acid transporters; EAATs) exist exclusively in abluminal membranes. The EAATs are secondary transporters that couple the Na⁺ gradient between the ECF and the endothelial cell to move glutamate against the existing electrochemical gradient. Thus, the EAATs in the abluminal membrane shift glutamate from the ECF to the endothelial cell where glutamate is free to diffuse into blood on facilitative carriers. This organization does not allow net glutamate entry to the brain; rather, it promotes the removal of glutamate and the maintenance of low glutamate concentrations in the ECF. This explains studies that show that the BBB is impermeable to glutamate, even at high concentrations, except in a few small areas that have fenestrated capillaries (circumventricular organs). Recently, the question of whether the BBB becomes permeable in diabetes has arisen. This issue was tested in rats with diet-induced obesity and insulin resistance or with streptozotocin-induced diabetes. Neither condition produced any detectable effect on BBB glutamate transport.

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