The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects
Abstract
The solute carrier family 1 (SLC1) includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively) as well as the two neutral amino acid transporters, ASCT1 and ASCT2 (SLC1A4 and ALC1A5, respectively). Although each of these transporters have similar predicted structures, they exhibit distinct functional properties which are variations of a common transport mechanism. The high-affinity glutamate transporters mediate transport of l-Glu, l-Asp and d-Asp, accompanied by the cotransport of 3 Na(+) and 1 H(+), and the countertransport of 1 K(+), whereas ASC transporters mediate Na(+)-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient. This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system. During pathological conditions, such as brain ischemia (e.g. after a stroke), however, glutamate exit can occur due to "reversed glutamate transport", which is caused by a reversal of the electrochemical gradients of the coupling ions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) may be of therapeutic interest to block glutamate release from neurons during ischemia. On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect mot…
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Alanine uptake may be mediated by either Slc1a4/SLC1A4 or Slc38a2/SLC38A2.
“Alanine uptake may be mediated by either Slc1a4/SLC1A4 (encoding the transporter ASCT1; Appendix Figure 11B,D) (329) or Slc38a2/SLC38A2 (encoding the transporter SNAT2; Appendix Figure 11C-D) (415).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [329]
EAAT3 operation involves outward transport of one K+ coupled to inward transport of 3 Na+ and one protonated glutamate.
“The operation of EAAT3 involves the outward transport of one K+ coupled to the inward transport of 3 Na+ and one protonated glutamate (329).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [329]
Both mouse and human β-cells express several members of the glutamate/neutral amino acid transporter family SLC1.
“Both mouse and human β-cells express several members of the glutamate/neutral amino acid transporter family SLC1 (329).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [329]
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Synaptic localization of GLT‐1a in the rat somatic sensory cortex
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“…for the largest proportion of total Glu transport and its functional inactivation raises extracellular Glu to toxic levels (Conti and Weinberg, 1999; Danbolt, 2001; Kanai and Hediger, 2004; Roth- stein et al., 1996; Rusakov et al., 1999; Torres and Amara, 2007; Tzingounis and Wadiche, 2007).”
BackgroundSamuels, J., Wang, Y., Riddle, M. A., Greenberg, B. D., Fyer, A. J., McCracken, J. T., Rauch, S. L., Murphy, D. L., Grados, M. A., Knowles, J. A., et al. (2011) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31184 · Cited by 89 · see citing works
Diversity of satellite glia in sympathetic and sensory gangliaPreprint
Mapps, A. A., Thomsen, M. B., Boehm, E. D., Zhao, H.-Q., Hattar, S., & Kuruvilla, R. (2021) · bioRxiv · doi:10.1101/2021.05.25.445647 · Cited by 89 · see citing works
“Sensory satellite glia Consistent with their association with glutamatergic neurons, one of the strongest markers of sensory satellite glia was Slc1a3 (Figures 3C, S4A, and S4B; Table S1H), a glutamate transporter that removes excess extracellular glutamate (Kanai and Hediger, 2004).”
BackgroundACE2 and gut amino acid transport.
Camargo, S., Vuille-Dit-Bille, R., Meier, C. F., & Verrey, F. (2020) · Clinical science · doi:10.1042/cs20200477 · Cited by 86 · see citing works
Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1.
Jensen, A. A., Erichsen, M. N., Nielsen, C., Stensbøl, T. B., Kehler, J., & Bunch, L. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm8013458 · Cited by 86 · see citing works
Baird, F. E., Bett, K. J., MacLean, C., Tee, A. R., Hundal, H. S., & Taylor, P. M. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00330.2009 · Cited by 83 · see citing works
Placental accommodations for transport and metabolism during intra-uterine crowding in pigs
Vallet, J. L., McNeel, A. K., Miles, J. R., & Freking, B. A. (2014) · Journal of Animal Science and Biotechnology/Journal of animal science and biotechnology · doi:10.1186/2049-1891-5-55 · Cited by 86 · see citing works
“A number of SLC genes are known transporters of amino acids including members of the SLC1, SLC3, SLC6, SLC7, SLC16, SLC36 and SLC38 gene families [70-76] (Table 1).”
BackgroundChanges in the expression of the glutamate transporter EAAT3/EAAC1 in health and disease
Bianchi, M., Bardelli, D., Chiu, M., & Bussolati, O. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1484-0 · Cited by 82 · see citing works
“eAAT3, the human counterpart of the eAAC1 rodent transporter, is a member of the eAAT family of high-affinity, sodium-dependent glutamate carriers encoded by genes of the SLC1 family [1–3].”
BackgroundAmmonium‐evoked alterations in intracellular sodium and pH reduce glial glutamate transport activity
Kelly, T., Kafitz, K. W., Roderigo, C., & Rose, C. (2009) · Glia · doi:10.1002/glia.20817 · Cited by 82 · see citing works
“Glial glutamate uptake is predominantly mediated by glutamate transporters EAAT1 and 2 (corresponding to GLAST and Glt-1 in rodents), which require the co-transport of one proton and three sodium ions and the counter-transport of one potassium ion (Danbolt, 2001; Kanai and Hediger, 2004).”
BackgroundCellular distribution of the neutral amino acid transporter subtype ASCT2 in mouse brain
Gliddon, C. M., Shao, Z., Stobart, J. L., & Anderson, C. M. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05767.x · Cited by 76 · see citing works
Regulation of renal amino acid transporters during metabolic acidosis.
Moret, C., Dave, M. H., Schulz, N., Jiang, J. X., Verrey, F., & Wagner, C. (2007) · AJP - Renal Physiology · doi:10.1152/ajprenal.00113.2006 · Cited by 80 · see citing works
“These transporters included members of three distinct families: the SLC1 family of glutamate transporters (20), the SLC3 and SLC7 families of heteromeric amino acid transporter subunits (33, 45, 49), and the SLC38 family of system A and N glutamine transporters (24).”
BackgroundMembrane transport metabolons.
Moraes, T., & Reithmeier, R. (2012) · Biochimica et Biophysica Acta · doi:10.1016/j.bbamem.2012.06.007 · Cited by 79 · see citing works
Lemos, M., Chiaia, H., Berton, M. P., Feitosa, F., Aboujaoud, C., Camargo, G. M., Pereira, A. S. C., Albuquerque, L., Ferrinho, A., Mueller, L., et al. (2016) · BMC Genomics · doi:10.1186/s12864-016-2511-y · Cited by 78 · see citing works
“The family of this gene includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively), also known as excitatory amino acid transporters (EAATs), which are sodium and potassium-dependent members of the solute carrier family 6 (SLC1) f…”
BackgroundNew views of glutamate transporter structure and function: advances and challenges
Jiang, J., & Amara, S. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.07.019 · Cited by 78 · see citing works
“The 5 mammalian EAATs and 2 ASCTs also belong to the solute carrier family 1 (SLC1), and correspond to the isoforms SLC1A1-7 (Kanai and Hediger, 2004).”
Chen, E. I., McClatchy, D. B., Park, S. K., & Yates, J. (2008) · Analytical Chemistry · doi:10.1021/ac800606w · Cited by 78 · see citing works
Paris, N., & Wong, E. A. (2013) · Poultry Science · doi:10.3382/ps.2012-02966 · Cited by 77
“The amino acid transporter EAAT3 (SLC1A1) is a Na+-dependent transporter located at the brushborder membrane, which has high affinity for anionic amino acids, including aspartate and glutamate (Kanai and Hediger, 2004).”
BackgroundHendriks, W. H., van Baal, J., & Bosch, G. (2012) · British Journal of Nutrition · doi:10.1017/s0007114512002395 · Cited by 76 · see citing works
“Two members of the high-affinity glutamate transporter family have been described: ASC transporter 1 (ASCT1) and ASCT2((28)).”
InfluentialMysona, B., Ying, D., Duplantier, J., Ganapathy, V., & Smith, S. B. (2009) · Cell and Tissue Research · doi:10.1007/s00441-008-0742-1 · Cited by 75 · see citing works
“In the retina, the main glutamate transporter expressed by Müller cells is GLAST (Kanai and Hediger 2004; Rauen et al. 1996).”
BackgroundOkazaki, S., Umene, K., Yamasaki, J., Suina, K., Otsuki, Y., Yoshikawa, M., Minami, Y., Masuko, T., Kawaguchi, S., Nakayama, H., et al. (2019) · Cancer Science · doi:10.1111/cas.14182 · Cited by 84 · see citing works
Widespread micro-RNA dysregulation in Multiple System Atrophy: disease-related alteration in miR-96
Ubhi, K., Rockenstein, E., Kragh, C., Inglis, C., Spencer, B., Michael, S., Mante, M., Adame, A., Galasko, D., & Masliah, E. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12444 · Cited by 74 · see citing works
“Of the SLC members predicted to be targets of miR-96, the neuronal/epithelial high-affinity glutamate transporter SLC1A1 (Kanai & Hediger, 2004) and the taurine transporter SLC6A6 (Anderson et al., 2009; Kristensen et al., 2011) appear on both the murine and human tables and may represent miR-96…”
BackgroundGlutathione is a physiologic reservoir of neuronal glutamate
Koga, M., Serritella, A. V., Messmer, M. M., Hayashi-Takagi, A., Hester, L. D., Snyder, S. H., Sawa, A., & Sedlak, T. W. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.04.087 · Cited by 73 · see citing works
“Substantial proportions of glutamate neurotransmitter pools (50-60%) have long thought to be derived from the glutamine-glutamate shuttle [16,17], with much smaller amounts arising from glycolysis [18-20].”
BackgroundThe glycine deportation system and its pharmacological consequences
Beyoğlu, D., & Idle, J. (2012) · Pharmacology and Therapeutics · doi:10.1016/j.pharmthera.2012.05.003 · Cited by 73 · see citing works
“The nature of the mitochondrial GLY transporter is unclear at present, although GLY appears to be a lowaffinity substrate for ASCT2 (SLC1A5) (Kanai & Hediger, 2004).”
BackgroundTransport of Amino Acids in the Kidney
Makrides, V., Camargo, S., & Verrey, F. (2014) · Comprehensive Physiology · doi:10.1002/j.2040-4603.2014.tb00550.x · Cited by 71 · see citing works
“It is caused by mutations in the SLC1A1 gene (chromosomal locus 9p24) encoding the glutamate and aspartate transporter EAAC1/EAAT3 (6, 97, 183).”
Structural ensemble of a glutamate transporter homologue in lipid nanodisc environment
Arkhipova, V., Guskov, A., & Slotboom, D. (2020) · Nature Communications · doi:10.1038/s41467-020-14834-8 · Cited by 70
Glutamate transporters in brain ischemia: to modulate or not?
Krzyżanowska, W., Pomierny, B., Filip, M., & Pera, J. (2014) · Acta Pharmacologica Sinica · doi:10.1038/aps.2014.1 · Cited by 70 · see citing works
Killeen, A., Morris, D., Kenny, D., Mullen, M., Diskin, M., & Waters, S. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-234 · Cited by 70 · see citing works
“As the name suggests SLC genes are involved in the transfer of solutes across the cell membrane, particularly amino acids [115-117].”
BackgroundPacher, M., Seewald, M., Mikula, M., Oehler, S., Mogg, M., Vinatzer, U., Eger, A., Schweifer, N., Varecka, R., Sommergruber, W., et al. (2007) · Carcinogenesis · doi:10.1093/carcin/bgl091 · Cited by 70 · see citing works
“The SLC1A4 transporter exchanges Na+ for small neutral amino acids such as Ala, Ser, Cys and Thr ( 48 ).”
BackgroundLactation and Its Hormonal Control
Anderson, S., MacLean, P., McManaman, J., & Neville, M. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-397175-3.00046-6 · Cited by 68 · see citing works
Nutrient Sensing: Another Chemosensitivity of the Olfactory System
Julliard, A., Koborssy, D. A., Fadool, D., & Palouzier-Paulignan, B. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00468 · Cited by 67 · see citing works
“The third transporter, SLC1A5, is an antiport that exchanges one Na+ and glutamine against neutral AAs in a 1:1 stoichiometry (Kanai and Hediger, 2004; Nicklin et al., 2009; Pochini et al., 2014).”
BackgroundDistribution of the glutamate transporters GLT-1 (SLC1A2) and GLAST (SLC1A3) in peripheral organs
Berger, U., & Hediger, M. (2006) · Anatomy and Embryology · doi:10.1007/s00429-006-0109-x · Cited by 67 · see citing works
“GLT-1 and GLAST remove glutamate from the brain extracellular fluid through co-transport of one glutamate molecule with three sodium ions and one proton ion, as well as the counter-transport of one potassium ion (Kanai and Hediger 2004).”
InfluentialSelf-citationYu, X., Plotnikova, O., Bonin, P., Subashi, T., McLellan, T. J., Dumlao, D., Che, Y., Dong, Y., Carpenter, E., West, G. M., et al. (2019) · eLife · doi:10.7554/elife.48120 · Cited by 66 · see citing works
“SLC1A5 (ASCT2) catalyzes an obligatory Na+-dependent antiport in which Na+ together with an extracellular neutral amino acid are exchanged with an intracellular neutral amino acid (Kanai and Hediger, 2004; Utsunomiya-Tate et al., 1996).”
Background
- Authors
- Kanai, Y., & Hediger, M. A.
- Affiliations
- Kyorin University (JP)
- Brigham and Women's Hospital (US)
- Corresponding author
- Hediger, Matthias A.
- Venue
- Pfl�gers Archiv European Journal of Physiology
- Published
- 2004-02-01
- Volume
- 447
- Issue
- 5
- Pages
- 469-479
- ISSN
- 0031-6768 (ISSN-L)
- 1432-2013
- OpenAlex
- W1998475753
- Cited by
- 450
- References
- 0
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 13 · 2023: 11 · 2022: 16 · 2021: 20 · 2020: 18 · 2019: 26 · 2018: 10 · 2017: 18 · 2016: 18 · 2015: 15 · 2014: 24 · 2013: 33 · 2012: 29
- FWCI
- 10.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Pflügers Archiv - European Journal of Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- glutamate transporters, neutral amino acid transporter, EAAC1, GLT-1, GLAST, EAAT4, ASCT1, ASCT2, glutamate excitotoxicity, cerebral ischemia, glutamate release, amyotrophic lateral sclerosis, motor neuron protection
- MeSH terms
- Animals, Biological Transport, Multigene Family, Humans, Glutamic Acid, Amino Acids, Neutral, Amino Acid Transport System X-AG
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