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Branched-Chain Amino Acids: Metabolism, Physiological Function, and Application: Session I

Structure of the Blood–Brain Barrier and Its Role in the Transport of Amino Acids^1–3,

Richard A. Hawkins^*,4, Robyn L. O'Kane, Ian A. Simpson^** and Juan R. Viña

^* Department of Physiology and Biophysics, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL; Natural and Applied Science Department, La Guardia Community College/CUNY, Long Island City, NY; ^** Department of Neural and Behavioral Sciences, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, PA; and Department of Biochemistry and Molecular Biology, Facultad de Medicina y Farmacia,Universidad de Valencia,Valencia, Spain

⁴ To whom correspondence should be addressed. E-mail: rah{at}post.harvard.edu.

ABSTRACT

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 (NAAs) on both membranes provides the brain access to essential AAs. 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 from there into 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 10% those of the plasma. Also present on the abluminal membrane are at least three Na⁺-dependent systems transporting acidic AAs (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 AAs from the brain and accounts for the low level of glutamate penetration into the central nervous system. The presence of a -glutamyl cycle at the luminal membrane and Na⁺-dependent AA transporters at the abluminal membrane may serve to modulate movement of AAs from blood to the brain. The -glutamyl cycle is expected to generate pyroglutamate (synonymous with oxyproline) within the endothelial cells. Pyroglutamate stimulates secondary active AA transporters at the abluminal membrane, thereby reducing the net influx of AAs to the brain. It is now clear that BBB participates in the active regulation of the AA content of the brain.

KEY WORDS: • brain capillaries • endothelial cells • polarity • sodium dependent transport • facilitative transport

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