title: Brain interstitial fluid glutamine homeostasis is controlled by blood-brain barrier SLC7A5/LAT1 amino acid transporter.
abstract: L-glutamine (Gln) is the most abundant amino acid in plasma and cerebrospinal fluid and a precursor for the main central nervous system excitatory (L-glutamate) and inhibitory (γ-aminobutyric acid (GABA)) neurotransmitters. Concentrations of Gln and 13 other brain interstitial fluid amino acids were measured in awake, freely moving mice by hippocampal microdialysis using an extrapolation to zero flow rate method. Interstitial fluid levels for all amino acids including Gln were ∼5-10 times lower than in cerebrospinal fluid. Although the large increase in plasma Gln by intraperitoneal (IP) injection of15N2-labeled Gln (hGln) did not increase total interstitial fluid Gln, low levels of hGln were detected in microdialysis samples. Competitive inhibition of system A (SLC38A1&2; SNAT1&2) or system L (SLC7A5&8; LAT1&2) transporters in brain by perfusion with α-(methylamino)-isobutyric acid (MeAIB) or 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) respectively, was tested. The data showed a significantly greater increase in interstitial fluid Gln upon BCH than MeAIB treatment. Furthermore, brain BCH perfusion also strongly increased the influx of hGln into interstitial fluid following IP injection consistent with transstimulation of LAT1-mediated transendothelial transport. Taken together, the data support the independent homeostatic regulation of amino acids in interstitial fluid vs. cerebrospinal fluid and the role of the blood-brain barrier expressed SLC7A5/LAT1 as a key interstitial fluid gatekeeper.
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology (ZIHP) and NCCR Kidney. CH, University of Zurich, Zurich, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Dolgodilina
authors.affiliation: Division of Psychiatry Research, University of Zurich, Schlieren, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Imobersteg
authors.affiliation: Functional Genomic Center Zurich (FGCZ), ETH and University of Zurich, Zurich, Switzerland.
authors.forename: Endre
authors.initials: E
authors.lastname: Laczko
authors.affiliation: Division of Psychiatry Research, University of Zurich, Schlieren, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Welt
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology (ZIHP) and NCCR Kidney. CH, University of Zurich, Zurich, Switzerland verrey@access.uzh.ch.
authors.forename: Francois
authors.initials: F
authors.lastname: Verrey
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology (ZIHP) and NCCR Kidney. CH, University of Zurich, Zurich, Switzerland.
authors.forename: Victoria
authors.initials: V
authors.lastname: Makrides
mesh_terms: D026924:Amino Acid Transport System A / Q000378:metabolism; D027182:Amino Acid Transport System y+ / Q000378:metabolism; D000598:Amino Acids, Cyclic / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism*; D027301:Fusion Regulatory Protein 1, Light Chains / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006706:Homeostasis; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D026924:Amino Acid Transport System A; D027182:Amino Acid Transport System y+; D000598:Amino Acids, Cyclic; D027301:Fusion Regulatory Protein 1, Light Chains; D027283:Large Neutral Amino Acid-Transporter 1; C518286:SLC7A8 protein, mouse; C432411:Slc38a1 protein, mouse; C498798:Slc38a2 protein, mouse; D005973:Glutamine; D015091:beta-Alanine; C012924:2,2-dimethyl-beta-alanine; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid
keywords: Blood–brain barrier; cerebrospinal fluid; glial cells; hippocampus; physiology