Neutral amino acid transport at the human blood-brain barrier

K. M. Hargreaves, W. M. Pardridge

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126 Scopus citations

Abstract

The kinetics of human blood-brain barrier neutral amino acid transport sites are described using isolated human brain capillaries as an in vitro model of the human blood-brain bazrrier. Kinetic parameters of transport (K(m), V(max), and K(D)) were determined for eight large neutral amino acids. K(m) values ranged from 0.30 ± 0.08 μM for phenylalanine to 8.8 ± 4.6 μM for valine. The amino acid analogs N-methylaminoisobutyric acid and 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid were used as model substrates of the alanine- and leucine-preferring transport systems, respectively. Phenylalanine is transported solely by the L-system (which is sensitive to 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid), and leucine is transported equally by the L- and ASC-system (which is sodium-dependent and N-methylaminoisobutyric acid-independent). Dose-dependent inhibition of the high affinity transport system by p-chloromercuribenzenesulfonic acid is demonstrated for phenylalanine, similar to the known sensitivity of blood-brain barrier transport in vivo. The K(m) values for the human brain capillary in vitro correlate significantly (r = 0.83, p < 0.01) with the K(m) values for the rat brain capillary in vivo. The results show that the affinity of human blood-brain barrier neutral amino acid transport is very high, i.e. very low K(m) compared to plasma amino acid concentrations. This provides a physical basis for the selective vulnerability of the human brain to derangements in amino acid availability caused by a selective hyperaminoacidemia, e.g. hyperphenylalaninemia.

Original languageEnglish (US)
Pages (from-to)19392-19397
Number of pages6
JournalJournal of Biological Chemistry
Volume263
Issue number36
StatePublished - Dec 1 1988
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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