Article Figures & Data
Figures
- 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.
- 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
Tables
- 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 Name Protein Name Aliases Substrates Transport Type/ Coupling Ions Tissue Distribution and Cellular/Subcellular Expression Relevant Molecular Mechanisms Sequence Accession ID SLC1A1 EAAC1, EAAC3 System X-AG Glutamate, asparagine C/Na+, H+, and k+ Brain (neurons), lung, colorectal, kidney, liver, heart, placenta IFN-β production: NF-κB pathway NM_004170 SLC1A2 GLT1, EAAT2 System X-AG Glutamate, asparagine C/Na+, H+, and k+ Brain (astrocytes, bergmann glia, neurons), liver, pancreas Akt/mTORC pathway: NF-κB pathway NM_004171 NM_001195728 NM_001252652 SLC1A3 GLAST, EAAT1 System X-AG Glutamate, asparagine C/Na+, H+, and k+ Brain (astrocytes, bergmann glia), heart, skeletal muscle, placenta NF-κB; IGF-1; TLR-3; IFN-β NM_004172 NM_001166695 NM_001166696 SLC1A4 ASCT1, SATT System ASC Cystine, serine, L-Threonine C/Na+, E/amino acids Widespread iNOS NM_003038 NM_001193493 SLC1A5 ASCT2, AAAT System ASC Asparagine, glutamine C/Na+, E/amino acids Adipose tissue, lung, skeletal muscle, large intestine, kidney, testis Lck phosphorylation; TCR signaling; NKG2D; IFN-γ production and degranulation NM_005638 NM_001145144 NM_001145145 SLC7A1 CAT-1 System y+ Arginine, lysine, ornithine F (non-obligatory E) Ubiquitous except for liver and lacrimal gland/basolateral and intracellular membranes in epithelial cells mTORC1 activity NM_003045 SLC7A2 CAT-2 System y+ Arginine, lysine, ornithine F CAT-2A: liver, skeletal muscle, pancreas; CAT-2B: inducible in many cell types NO production; NF-κB pathway NM_003046 NM_001008539 SLC7A5 LAT1 System L Glutamine, leucine, methionine, tryptophan E (similar intra- and extracellular selectivities, lower intracellular apparent affinity) Brain, ovary, testis, placenta, spleen, colon, blood-brain barrier, fetal liver, activated lymphocytes, tumor cells c-Myc expression; IFN-γ production and granzyme B expression NM_003486 SLC7A7 y+LAT1 system y+L Lysine, arginase, ornithine, methionine, leucine Na+ dependent transport of extracellular large neutral L-amino acids Small intestine, kidney, spleen, leukocytes, placenta, lung/basolateral in epithelial cells NO production; NF-κB pathway NM_003982 SLC7A11 xCT system xc- Cystine, glutamate E (preferentially extracellular cystine against intracellular glutamate) Macrophages, brain, retinal pigment cells, liver, kidney/basolateral in epithelial cells Glutathione production; ROS accumulation; mTOR and NFAT activity; glycolysis and glutaminolysis NM_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.
Human Gene Name Inhibitor Formula IC50 Reference SLC1A2 WAY-213613 C16H14BrClF2N2O4 0.085 μM (Simmons et al., 2014) DL-TBOA C11H13NO5 6 μM (Pedraz-Cuesta et al., 2015) Dihydrokainic acid (DHK) C10H17NO4 23 µM(Ki) (Arriza et al., 1994) T3MG C6H11NO4 90 µM (Eliasof et al., 2001) SLC1A3 UCPH-101 C27H22N2O3 0.66 μM (Abrahamsen et al., 2013) UCPH-102 C21H18N2O2 0.42 μM (Haym et al., 2016) DL-TBOA C11H13NO5 70 μM (Shimamoto et al., 1998) WAY-213613 C16H13BrF2N2O4 5 μM (Hashimoto et al., 2018; Tao et al., 2020) SLC1A5 Lobetyolin C20H28O8 N/A (He et al., 2020) V-9302 C34H38N2O4 9.6 μM (Schulte et al., 2018) GPNA hydrochloride C11H14ClN3O5 55 μM(Ki) (Corti et al., 2019) SLC7A2 Platonin N/A N/A (Chen et al., 2006) SLC7A5 BCH C8H13NO2 131.5 µM (Fraga et al., 2002; Kim et al., 2002) KMH-233 C32H25N7O5 18 μM (Huttunen et al., 2016) GPNA hydrochloride C11H14ClN3O5 250 μM. (Corti et al., 2019) Lats-IN-1 C18H14N4OS 0.51 μM (EC50) (Kastan et al., 2021) JPH203 C23H19Cl2N3O4 0.14 μM (Oda et al., 2010) GPNA, L-γ-Glutamyl-p-nitroanilide.
