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      Analysis of L-leucine amino acid transporter species activity and gene expression by human blood brain barrier hCMEC/D3 model reveal potential LAT1, LAT4, B 0AT2 and y +LAT1 functional cooperation


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          In the CNS, amino acid (AA) neurotransmitters and neurotransmitter precursors are subject to tight homeostatic control mediated by blood-brain barrier (BBB) solute carrier amino acid transporters (AATs). Since the BBB is composed of multiple closely apposed cell types and opportunities for human in vivo studies are limited, we used in vitro and computational approaches to investigate human BBB AAT activity and regulation. Quantitative real-time PCR (qPCR) of the human BBB endothelial cell model hCMEC/D3 (D3) was used to determine expression of selected AAT, tight junction (TJ), and signal transduction (ST) genes under various culture conditions. L-leucine uptake data were interrogated with a computational model developed by our group for calculating AAT activity in complex cell cultures. This approach is potentially applicable to in vitro cell culture drug studies where multiple “receptors” may mediate observed responses. Of 7 Leu AAT genes expressed by D3 only the activity of SLC7A5-SLC3A2/LAT1-4F2HC (LAT1), SLC43A2/LAT4 (LAT4) and sodium-dependent AATs, SLC6A15/B 0AT2 (B 0AT2), and SLC7A7/y +LAT1 (y +LAT1) were calculated to be required for Leu uptake. Therefore, D3 Leu transport may be mediated by a potentially physiologically relevant functional cooperation between the known BBB AAT, LAT1 and obligatory exchange (y +LAT1), facilitative diffusion (LAT4), and sodium symporter (B 0AT2) transporters.

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              Antigen receptor control of amino acid transport coordinates the metabolic re-programming that is essential for T cell differentiation

              Summary T lymphocytes regulate nutrient uptake to meet the metabolic demands of immune activation. The present study shows that the intracellular supply of large neutral amino acids (LNAAs) in T cells is regulated by pathogen and the T cell antigen receptor (TCR). A single System L transporter, Slc7a5, mediated LNAA uptake in activated T cells. Slc7a5-null T cells could not metabolically reprogram in response to antigen and failed clonal expansion and effector differentiation. The metabolic catastrophe caused by Slc7a5 loss reflects the requirement for sustained uptake of the LNAA leucine for activation of mammalian target of rapamycin complex 1 (mTORC1) and for expression of c-myc. Pathogen control of System L transporters is thus a critical metabolic checkpoint for T cells.

                Author and article information

                J Cereb Blood Flow Metab
                J Cereb Blood Flow Metab
                Journal of Cerebral Blood Flow & Metabolism
                SAGE Publications (Sage UK: London, England )
                24 August 2021
                January 2022
                24 August 2021
                : 42
                : 1
                : 90-103
                [1 ]The Interface Group, Institute of Physiology, University of Zürich, Zürich, Switzerland
                [2 ]Epithelial Transport Group, Institute of Physiology, University of Zürich, Zürich, Switzerland
                [3 ]Department of Intensive Care Medicine, University Hospital, University of Bern, Bern, Switzerland
                [4 ]National Center of Competence in Research, Kidney CH, Switzerland
                [5 ]EIC BioMedical Labs, Norwood, MA, USA
                Author notes

                These authors contributed equally to this work.

                [*]Victoria Makrides, The Interface Group, University of Zürich, Institute of Physiology, Winterthurstr 190, CH-8057 Zürich, Switzerland. Email: makrides@ 123456access.uzh.ch
                © The Author(s) 2021

                This article is distributed under the terms of the Creative Commons Attribution 4.0 License ( https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                : 19 April 2021
                : 6 July 2021
                : 12 July 2021
                Original Articles
                Custom metadata

                blood-brain barrier,computational model,insulin-like growth factor 1,hcmec/d3,solute carrier amino acid transporters


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