Blood-brain barrier neutral amino acid carrier

Greig NH, Momma S, Sweeney DJ, et al. Facilitated transport of melphalan at the rat blood-brain barrier by the large neutral amino acid carrier system. Cancer Res 1987 47 1571-1576. 

The other major class of transporter protein is the carrier protein. A prototypic example of a carrier protein is the large neutral amino acid transporter. An important function of the LNAA transporter is to transport molecules across the blood-brain barrier. As discussed previously, most compounds cross the BBB by passive diffusion. However, the brain requires certain compounds that are incapable of freely diffusing across the BBB phenylalanine and glucose are two major examples of such compounds. The LNAA serves to carry phenylalanine across the BBB and into the central nervous system. Carrier proteins, such as the LNAA transporter, can be exploited in drug design. For example, highly polar molecules will not diffuse across the BBB. However, if the pharmacophore of this polar molecule is covalently bonded to another molecule which is a substrate for the LNAA, then it is possible that the pharmacophore will be delivered across the BBB by hitching a ride on the transported molecule. 

Three major factors are considered as important in determining the supply of tryptophan to the brain leading to serotonin synthesis (1) the extent of binding of tryptophan to serum albumin, which influences the pool of free (unbound) tryptophan that interacts with the amino acid carrier mechanism located at the blood-brain barrier, (2) the plasma tryptophan concentrations, and (3) the plasma concentration of other large neutral amino acids (LNAA), which compete with tryptophan for uptake into brain. Each factor can be influenced by the nutritional or hormonal status of the host and also by interorgan relationships in the metabolism of amino acids. 

The entry of small neutral amino acids, such as alanine, glycine, proline, and 7-aminobutyrate (GABA), is markedly restricted because their influx could dramatically change the content of neurotransmitters (see section 111). They are synthesized in the brain, and some are transported out of the CNS and into the blood via the A-(alanine-preferring)-system carrier. Vitamins have specific transporters through the blood-brain barrier as they do in most tissues. 

In liver failure the plasma concentrations of the aromatic amino acids (AAAs) tyrosine, phenylalanine, and tryptophan increase, probably because they are predominantly broken down in the liver, whereas the plasma levels of BCAAs decrease while they are degraded in excess in muscle as a consequence of hepatic failure-induced catabolism. As AAAs and BCAAs are all neutral amino acids and share a common transporter across the blood-brain barrier (system L carrier), changes in their plasma ratio are reflected in the brain, subsequently disrupting the neurotransmitter profile of the catecholamines and indoleamines (see sections on tyrosine and tryptophan). It has been hypothesized that this disturbance contributes to the multifactorial pathogenesis of hepatic encephalopathy. In line with this hypothesis it has been suggested that normalization of the amino acid pattern by supplementing extra BCAAs counteracts hepatic encephalopathy. 

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