11
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          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.

          Related collections

          Most cited references59

          • Record: found
          • Abstract: found
          • Article: not found

          mTOR signaling in growth control and disease.

          The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation. Copyright © 2012 Elsevier Inc. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Astrocyte-endothelial interactions at the blood-brain barrier.

            The blood-brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood-brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              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.
                Bookmark

                Author and article information

                Journal
                J Cereb Blood Flow Metab
                J Cereb Blood Flow Metab
                JCB
                spjcb
                Journal of Cerebral Blood Flow & Metabolism
                SAGE Publications (Sage UK: London, England )
                0271-678X
                1559-7016
                24 August 2021
                January 2022
                24 August 2021
                : 42
                : 1
                : 90-103
                Affiliations
                [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
                Article
                10.1177_0271678X211039593
                10.1177/0271678X211039593
                8721536
                34427144
                e361d56f-e62e-4408-83a1-3e3e5ae85d8e
                © 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).

                History
                : 19 April 2021
                : 6 July 2021
                : 12 July 2021
                Categories
                Original Articles
                Custom metadata
                ts2

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

                Comments

                Comment on this article