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Review ArticleSpecial Section on New Era of Transporter Science: Unraveling the Functional Role of Orphan Transporters
Open Access

Amino Acid Solute Carrier Transporters in Inflammation and Autoimmunity

Linlin Sheng, Qi Luo and Ligong Chen
Drug Metabolism and Disposition September 2022, 50 (9) 1228-1237; DOI: https://doi.org/10.1124/dmd.121.000705
Linlin Sheng
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, China (L.S., Q.L., L.C.); Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (L.C.); and Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China (L.C.)
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Qi Luo
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, China (L.S., Q.L., L.C.); Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (L.C.); and Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China (L.C.)
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Ligong Chen
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, China (L.S., Q.L., L.C.); Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (L.C.); and Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China (L.C.)
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    Fig. 1.

    Proposed roles of SLC1A1, SLC1A2, and SLC1A3 in the CNS. In neurons, glutaminase catalyzes the breakdown of glutamine (purple circle) to glutamate (green circle), which is transported illlllnto vesicles by VGLUTs and released into the synaptic space. SLC1A1, SLC1A2 reuptake glutamate into neurons, and SLC1A2, SLC1A3 uptake glutamate into astrocytes, preventing excitotoxicity. Astrocytic glutamine is synthesized from glutamate catalyzed by GS, and then used by neurons. Agents that have been reported to stimulate or inhibit SLC1A1, SLC1A2, and SLC1A3 are presented. Microglia upon activation releases glutamate. VGLUTs, vesicular glutamate transporters.

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    Fig. 2.

    Proposed roles of SLC7 transporters in immune cells. In T cells, SLC7A1 transports arginine; SLC7A5/CD98 transports leucine, methionine, tryptophan, and other amino acids; and SLC7A11 transports glutamate. Leucine is essential for mTORC1 activation and c-Myc maintenance, and methionine is necessary for protein synthesis. Suppression of T cells by MDSCs is abolished by SLC7A2 deficiency. GSH production in part mediated by SLC7A11 can limit ROS accumulation and support the activity of mTOR and nuclear factor of activated T cells to drive glycolysis and glutaminolysis in activated T cells. Leucine is also required for NK cells. In macrophages, M1 or M2 activation both induce SLC7A2/CD98-dependent arginine transport. Mutation of SLC7A7 causes LPI and lowers phagocytic activity and NO production of macrophages. SLC7A11/CD98 transports cysteine and could be induced by M2 activation. SLC7A2 deficiency in colon causes more severe AOM-DSS-induced colitis and favors M2 macrophage activation. UC reduced chromosome-associated protein D3 upregulating SLC7A5/CD98 expression. AAs, amino acids; AOM-DSS, azoxymethane-dextran sulfate sodium; GSH, glutathione; ROS, reactive oxygen species. * Figure created in biorender.com

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    TABLE 1

    SLC1 and SLC7: two amino acid solute carrier transporter families related to inflammation and autoimmunity

    For detailed information about the SLC genes, please visit: http://www.bioparadigms.org.

    Human Gene NameProtein NameAliasesSubstratesTransport Type/ Coupling IonsTissue Distribution and Cellular/Subcellular ExpressionRelevant Molecular MechanismsSequence Accession ID
    SLC1A1EAAC1, EAAC3System X-AGGlutamate, asparagineC/Na+, H+, and k+Brain (neurons), lung, colorectal, kidney, liver, heart, placentaIFN-β production: NF-κB pathwayNM_004170
    SLC1A2GLT1, EAAT2System X-AGGlutamate, asparagineC/Na+, H+, and k+Brain (astrocytes, bergmann glia, neurons), liver, pancreasAkt/mTORC pathway: NF-κB pathwayNM_004171 NM_001195728 NM_001252652
    SLC1A3GLAST, EAAT1System X-AGGlutamate, asparagineC/Na+, H+, and k+Brain (astrocytes, bergmann glia), heart, skeletal muscle, placentaNF-κB; IGF-1; TLR-3; IFN-βNM_004172 NM_001166695 NM_001166696
    SLC1A4ASCT1, SATTSystem ASCCystine, serine, L-ThreonineC/Na+, E/amino acidsWidespreadiNOSNM_003038 NM_001193493
    SLC1A5ASCT2, AAATSystem ASCAsparagine, glutamineC/Na+, E/amino acidsAdipose tissue, lung, skeletal muscle, large intestine, kidney, testisLck phosphorylation; TCR signaling; NKG2D; IFN-γ production and degranulationNM_005638 NM_001145144 NM_001145145
    SLC7A1CAT-1System y+Arginine, lysine, ornithineF (non-obligatory E)Ubiquitous except for liver and lacrimal gland/basolateral and intracellular membranes in epithelial cellsmTORC1 activityNM_003045
    SLC7A2CAT-2System y+Arginine, lysine, ornithineFCAT-2A: liver, skeletal muscle, pancreas; CAT-2B: inducible in many cell typesNO production; NF-κB pathwayNM_003046 NM_001008539
    SLC7A5LAT1System LGlutamine, leucine, methionine, tryptophanE (similar intra- and extracellular selectivities, lower intracellular apparent affinity)Brain, ovary, testis, placenta, spleen, colon, blood-brain barrier, fetal liver, activated lymphocytes, tumor cellsc-Myc expression; IFN-γ production and granzyme B expressionNM_003486
    SLC7A7y+LAT1system y+LLysine, arginase, ornithine, methionine, leucineNa+ dependent transport of extracellular large neutral L-amino acidsSmall intestine, kidney, spleen, leukocytes, placenta, lung/basolateral in epithelial cellsNO production; NF-κB pathwayNM_003982
    SLC7A11xCTsystem xc-Cystine, glutamateE (preferentially extracellular cystine against intracellular glutamate)Macrophages, brain, retinal pigment cells, liver, kidney/basolateral in epithelial cellsGlutathione production; ROS accumulation; mTOR and NFAT activity; glycolysis and glutaminolysisNM_014331
    • Akt, protein kinase B; ASCT, alanine serine cysteine transporter; C, cotransporter; E, exchanger; F, facilitated transporter.; IGF, Insulin-Like Growth Factor; NFAT, nuclear factor of activated T cells; NKG2D, natural killer group 2, member D; xCT, Solute Carrier Family 7 Member 11; xc-, cystine/glutamate antiporter.

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    TABLE 2

    Specific inhibitors associated with SLC1 and SLC7 transporters

    Human Gene NameInhibitorFormulaIC50Reference
    SLC1A2WAY-213613C16H14BrClF2N2O40.085 μM(Simmons et al., 2014)
    DL-TBOAC11H13NO56 μM(Pedraz-Cuesta et al., 2015)
    Dihydrokainic acid (DHK)C10H17NO423 µM(Ki)(Arriza et al., 1994)
    T3MGC6H11NO490 µM(Eliasof et al., 2001)
    SLC1A3UCPH-101C27H22N2O30.66 μM(Abrahamsen et al., 2013)
    UCPH-102C21H18N2O20.42 μM(Haym et al., 2016)
    DL-TBOAC11H13NO570 μM(Shimamoto et al., 1998)
    WAY-213613C16H13BrF2N2O45 μM(Hashimoto et al., 2018; Tao et al., 2020)
    SLC1A5LobetyolinC20H28O8N/A(He et al., 2020)
    V-9302C34H38N2O49.6 μM(Schulte et al., 2018)
    GPNA hydrochlorideC11H14ClN3O555 μM(Ki)(Corti et al., 2019)
    SLC7A2PlatoninN/AN/A(Chen et al., 2006)
    SLC7A5BCHC8H13NO2131.5 µM(Fraga et al., 2002; Kim et al., 2002)
    KMH-233C32H25N7O518 μM(Huttunen et al., 2016)
    GPNA hydrochlorideC11H14ClN3O5250 μM.(Corti et al., 2019)
    Lats-IN-1C18H14N4OS0.51 μM (EC50)(Kastan et al., 2021)
    JPH203C23H19Cl2N3O40.14 μM(Oda et al., 2010)
    • GPNA, L-γ-Glutamyl-p-nitroanilide.

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Drug Metabolism and Disposition: 50 (9)
Drug Metabolism and Disposition
Vol. 50, Issue 9
1 Sep 2022
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Review ArticleSpecial Section on New Era of Transporter Science: Unraveling the Functional Role of Orphan Transporters

Amino Acid Transporters in Immunity

Linlin Sheng, Qi Luo and Ligong Chen
Drug Metabolism and Disposition September 1, 2022, 50 (9) 1228-1237; DOI: https://doi.org/10.1124/dmd.121.000705

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Review ArticleSpecial Section on New Era of Transporter Science: Unraveling the Functional Role of Orphan Transporters

Amino Acid Transporters in Immunity

Linlin Sheng, Qi Luo and Ligong Chen
Drug Metabolism and Disposition September 1, 2022, 50 (9) 1228-1237; DOI: https://doi.org/10.1124/dmd.121.000705
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