Cited by 450Amino Acid Enzymes and MetabolismNeuroscience and Neuropharmacology ResearchIon Transport and Channel Regulation

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The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects

Kanai, Yoshikatsu, Hediger, Matthias A.·2004·Pfl�gers Archiv European Journal of Physiology

DOI 10.1007/s00424-003-1146-4

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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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Hatakeyama, D., Mita, K., Kobayashi, S., Sadamoto, H., Fujito, Y., Hiripi, L., Elekes, K., & Ito, E. (2009) · Journal of Neuroscience Research · doi:10.1002/jnr.22296 · Cited by 10
The Transport Systems of the Blood–Brain Barrier
Zhang, W.-D., & Stanimirovic, D. (2005) · CRC Press eBooks · doi:10.1201/b14290-7 · Cited by 10
Specialized Neurotransmitter Transporters in Astrocytes
Yang, Y., & Rothstein, J. D. (2008) · Springer eBooks · doi:10.1007/978-0-387-79492-1_4 · Cited by 9
Genome‐Scale Modeling of CHO Cells Unravel the Critical Role of Asparagine in Cell Culture Feed Media
Pang, K., Hong, Y.-F., Shozui, F., Furomitsu, S., Myint, M., Ho, Y., Silberberg, Y. R., Walsh, I., & Lakshmanan, M. (2024) · Biotechnology Journal · doi:10.1002/biot.202400072 · Cited by 9
Identification of a novel model based on ferroptosis-related genes for predicting the prognosis of diffuse large B-cell lymphomas
Wang, J.-Y., Peng, H.-L., Zhang, G.-S., & Yan, W.-Z. (2023) · Hematology · doi:10.1080/16078454.2023.2198862 · Cited by 9
“SLC1A5 is a cell surface solute-carrying transporter that facilitates the uptake of neutral amino acids [44].”
Background
Logistic ridge regression to predict bipolar disorder using mRNA expression levels in the N-methyl-D-aspartate receptor genes.
Lin, E., Lin, C.-H., & Lane, H.-Y. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.10.081 · Cited by 9
The segregation of different submicroscopic imbalances underlying the clinical variability associated with a familial karyotypically balanced translocation
Fonseca, A. C. S., Bonaldi, A., Fonseca, S. A. S., Otto, P., Kok, F., Bak, M., Tommerup, N., & Vianna-Morgante, A. (2015) · Molecular Cytogenetics · doi:10.1186/s13039-015-0205-9 · Cited by 9
“SLC1A4 encodes a neutral small amino acid transporter, and is ubiquitously expressed [21], particularly in glial cells, and during brain development [22].”
Downregulation of solute carriers of glutamate in gliosomes and synaptosomes may explain local brain metastasis in anaplastic glioblastoma
Tong, H.-Y., Yu, X.-G., Lu, X.-C., & Wang, P. (2015) · IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology · doi:10.1002/iub.1372 · Cited by 9
A SLC6 transporter of the novel B0,- system aids in absorption and detection of nutrient amino acids in Caenorhabditis elegans
Metzler, R., Meleshkevitch, E. A., Fox, J. M., Kim, H., & Boudko, D. Y. (2013) · Journal of Experimental Biology · doi:10.1242/jeb.081497 · Cited by 9
“The acidic amino acids are substrates of phylogenetically and structurally distinct transporters of the SLC1 family (Kanai and Hediger, 2004).”
Background
cDNA sequence and tissue distribution of canine Na-dependent neutral amino acid transporter 2 (ASCT 2).
Ochiai, H., Onda, K., Ogihara, K., Naya, Y., Sugiyama, H., & Maruo, T. (2012) · Journal of Veterinary Medical Science · doi:10.1292/jvms.12-0171 · Cited by 9
“This designation is now attributed to 2 Na+-dependent transporters termed ASCT1 and ASCT2 (System ASC amino acid transporters 1 and 2, respectively), which belong to the SLC1 gene family [10, 18].”
Background
Identification of variation in the platelet transcriptome associated with Glycoprotein 6 haplotype
Burns, P., Gusnanto, A., Macaulay, I., Rankin, A., Tom, B., Langford, C., Dudbridge, F., Ouwehand, W., & Watkins, N. (2008) · Platelets · doi:10.1080/09537100801947434 · Cited by 9
“The next highest ratio was 11-fold for SLC1A7, a membrane bound glutamate transporter [25].”
Background
Transport of D-[1-14C]-amino acids into Chinese hamster ovary (CHO-K1) cells: implications for use of labeled d-amino acids as molecular imaging agents.
Shikano, N., Nakajima, S., Kotani, T., Ogura, M., Sagara, J., Iwamura, Y., Yoshimoto, M., Kubota, N., Ishikawa, N., & Kawai, K. (2007) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2007.05.001 · Cited by 9
“Recent molecular biology studies of amino acid transport have revealed much about solute carrier (SLC) genes, which are the genes encoding proteins that transport substances found in liquids [18–20].”
Background
Studying amino acid transport using liposomes.
Indiveri, C. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-447-0_5 · Cited by 9
The importance of company: Na+ and Cl- influence substrate interaction with SLC6 transporters and other proteins.
Reith, M., Zhen, J., & Chen, N. (2006) · Handbook of Experimental Pharmacology · doi:10.1007/3-540-29784-7_4 · Cited by 9
“Ser440 is located at the extracellular face of the re-entrant loop between TM7 and 8, likely close to the binding site for glutamate (see Kanai and Hediger 2004, and see below: the crystal structure of the archaeal glutamate transporter homolog).”
Background
Disruption of glutamine transport uncouples the NUPR1 stress-adaptation program and induces prostate cancer radiosensitivity
Kahya, U., Lukiyanchuk, V., Gorodetska, I., Weigel, M. M., Köseer, A. S., Alkan, B., Savic, D., Linge, A., Löck, S., Peitzsch, M., et al. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02344-3 · Cited by 7
“SLC1A5 primarily mediates Gln uptake, while SLC7A5 functions as a bidirectional transporter facilitating the exchange of intracellular Gln for extracellular essential amino acids, including leucine [39–42].”
Strategies for Successful Over-Expression of Human Membrane Transport Systems Using Bacterial Hosts: Future Perspectives
Galluccio, M., Console, L., Pochini, L., Scalise, M., Giangregorio, N., & Indiveri, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073823 · Cited by 10
Evaluation of cell‐free protein synthesis for the crystallization of membrane proteins – a case study on a member of the glutamate transporter family from Staphylothermus marinus
Jaehme, M., & Michel, H. (2013) · The FEBS Journal · doi:10.1111/febs.12105 · Cited by 8
Preclinical characterization of 18F-D-FPHCys, a new amino acid-based PET tracer
Denoyer, D., Kirby, L., Waldeck, K., Roselt, P., Neels, O. C., Bourdier, T., Shepherd, R., Katsifis, A., & Hicks, R. (2012) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-011-2017-4 · Cited by 8
CATALYTIC RECEPTORS
Alexander, S. P. H., Mathie, A., & Peters, J. (2011) · doi:10.1111/j.1476-5381.2011.01649_7.x · Cited by 8
“…acid transporters Overview: The SLC1 family of sodium dependent transporters includes the plasma membrane located glutamate transporters and the neutral amino acid transporters ASCT1 and ASCT2 (Amara and Arriza, 1993; Palacín et al., 1998; Kanai and Hediger, 2003; 2004; Beart and O’Shea, 2007).”
Background
Maintenance of antioxidant defenses of brain cells: plasma membrane glutamate transporters and beyond
Had‐Aissouni, L. (2011) · Amino Acids · doi:10.1007/s00726-011-0860-z · Cited by 8
“Therefore, the EAAT3/ EAAC1 gene is called Slc1a1; the EAAT2/GLT-1 (glutamate transporter-1) gene, Slc1a2; the EAAT1/GLAST gene, Slc1a3; the EAAT4 gene, Slc1a6 and the EAAT5 gene, Slc1a7 (Kanai and Hediger 2004).”
Membrane transporters and the diseases corresponding to functional defects
Lai, Y. (2013) · Elsevier eBooks · doi:10.1533/9781908818287.1 · Cited by 13
Co-Expression Network Analysis and Molecular Docking Demonstrate That Diosgenin Inhibits Gastric Cancer Progression via SLC1A5/mTORC1 Pathway
Cui, N., & Ding, F. (2024) · Drug Design, Development and Therapy · doi:10.2147/dddt.s458613 · Cited by 7
Association Between the SLC1A1 Glutamate Transporter Gene and Obsessive-Compulsive Disorder in the Chinese Han Population
Huang, X., Liu, J., Cong, J., & Zhang, X. (2021) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s281623 · Cited by 11
“SLC1A1 is located on chromosome 9p24, which is expressed in brain regions related to OCD,(14) including the cerebral cortex, striatum, and thalamus.(15) As research into the hereditary pattern of OCD increases, the role of the glutamate transporter gene SLC1A1 in the pathogenesis of the disease has attracted attention.”
Background
Exercise pre‑conditioning alleviates brain damage via excitatory amino acid transporter 2 and extracellular signal‑regulated kinase 1/2 following ischemic stroke in rats.
Wang, X., Zhang, M., Feng, R., Li, W.-B., Ren, S., & Zhang, F. (2014) · Molecular Medicine Reports · doi:10.3892/mmr.2014.2834 · Cited by 7
A single nucleotide polymorphism in SLC1A1 gene is associated with age of onset of obsessive-compulsive disorder
Dallaspezia, S., Mazza, M. G., Lorenzi, C., Benedetti, F., & Smeraldi, E. (2014) · European Psychiatry · doi:10.1016/j.eurpsy.2014.02.006 · Cited by 7
Radioiodinated 4-iodo-L-meta-tyrosine, a system L selective artificial amino acid: molecular design and transport characterization in Chinese hamster ovary cells (CHO-K1 cells).
Shikano, N., Kotani, T., Nakajima, S., Ogura, M., Nakazawa, S., Sagara, J., Kobayashi, M., Baba, T., Yamaguchi, N., Kubota, N., et al. (2010) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2010.06.006 · Cited by 7
The glutamate transporter excitatory amino acid carrier 1 associates with the actin-binding protein alpha-adducin.
Bianchi, M., Gatti, R., Torielli, L., Padoani, G., Gazzola, G., & Bussolati, O. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.05.029 · Cited by 7
Stimulation of 125I-3-iodo-alpha-methyl-L-tyrosine uptake in Chinese hamster ovary (CHO-K1) cells by tyrosine esters.
Shikano, N., Ogura, M., Sagara, J., Nakajima, S., Kobayashi, M., Baba, T., Yamaguchi, N., Iwamura, Y., Kubota, N., & Kawai, K. (2010) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2009.10.003 · Cited by 7
“Uptake into cells of (11)C-methionine and IMT has been reported to differ considerably depending on whether the cells are in the growth phase or the confluent phase [11].”
Background
Technologies for transporter drug discovery
Weinglass, A. B., Kaczorowski, G., & García, M. (2008) · Channels · doi:10.4161/chan.2.5.6896 · Cited by 7
Cranberry Proanthocyanidins Mitigate Reflux-Induced Transporter Dysregulation in an Esophageal Adenocarcinoma Model
Zhang, Y., Weh, K. M., Tripp, B. A., Clarke, J. L., Howard, C. L., Sunilkumar, S., Howell, A. B., & Kresty, L. (2023) · Pharmaceuticals · doi:10.3390/ph16121697 · Cited by 6
“To date, studies have reported transporter dysregulation correlated with progression to EAC, therapeutic resistance or poor patient prognosis [43,46,47,50,51,53–55,61 –66 Aquaporin transporters are multimeric channel proteins composed of two subfamilies that transport either water alone or water…”
Background
Glutamatergic pathways in the brains of turtles: A comparative perspective among reptiles, birds, and mammals
Hussan, M. T., Sakai, A., & Matsui, H. (2022) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2022.937504 · Cited by 14
Identify an innovative ferroptosis‐related gene in hepatocellular carcinoma
Hu, G.-F., Huang, X., Zhang, B., Gao, P., Wu, W., & Wang, J. (2022) · Journal of clinical laboratory analysis (Print) · doi:10.1002/jcla.24632 · Cited by 6

Authors: Kanai, Y., & Hediger, M. A.
Affiliations: Kyorin University (JP)
Brigham and Women's Hospital (US)
Corresponding author: Hediger, Matthias A.
ORCID: Kanai, Yoshikatsu
Hediger, Matthias A.
Venue: Pfl�gers Archiv European Journal of Physiology
Publisher: Springer Science and Business Media LLC
Published: 2004-02-01
Volume: 447
Issue: 5
Pages: 469-479
ISSN: 0031-6768 (ISSN-L)
1432-2013
DOI: 10.1007/s00424-003-1146-4
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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The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects

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