The Role of Blood-Brain Barrier Transport of Tryptophan and Other Neutral Amino Acids in the Regulation of Substrate-Limited Pathways of Brain Amino Acid Metabolism

Abstract

Many pathways of essential neutral amino acid metabolism in the CNS are influenced by precursor availability. Since the delivery of circulating amino acids to brain cells is primarily controlled by the rate of amino acid transport through the blood-brain barrier (BBB), pathways of brain amino acid metabolism are ultimately influenced by the activity (K_m, V_max) of the BBB neutral amino acid transport system. The K_m of BBB transport is in the 0.1–0.6 mM range, which approximates the physiologic plasma levels and forms the basis of the unusual sensitivity of the brain to competition effects on neutral amino acid transport. Unlike the brain, the K_m of amino acid transport into other organs is in the 1–10 mM range or greater, which frees these tissues from competition effects in the physiologic range of plasma amino acids. Tryptophan circulates 80–90% bound to albumin; however, the capacity/affinity ratio of the BBB neutral amino acid transport system exceeds the capacity/affinity ratio of albumin binding of tryptophan, which enables the carrier to strip tryptophan off albumin as it traverses the brain capillary. The activity of the BBB neutral amino acid transport system is probably not modulated by insulin, but is influenced by changes in thyroid hormone status; the transport system is also induced in states of hepatic encephalopathy and this induction process is the primary cause of the increased brain tryptophan and serotonin levels in cirrhosis.