Excitatory amino acid transporter 1

Excitatory amino acid transporter 1 (EAAT1) is a protein that, in humans, is encoded by the SLC1A3 gene.[5] EAAT1 is also often called the GLutamate ASpartate Transporter 1 (GLAST-1).

SLC1A3
Identifiers
AliasesSLC1A3, EA6, EAAT1, GLAST, GLAST1, solute carrier family 1 member 3
External IDsOMIM: 600111 MGI: 99917 HomoloGene: 20882 GeneCards: SLC1A3
Orthologs
SpeciesHumanMouse
Entrez

6507

20512

Ensembl

ENSG00000079215

ENSMUSG00000005360

UniProt

P43003

P56564

RefSeq (mRNA)

NM_001166695
NM_001166696
NM_001289939
NM_001289940
NM_004172

NM_148938

RefSeq (protein)

NP_001160167
NP_001160168
NP_001276868
NP_001276869
NP_004163

NP_683740

Location (UCSC)Chr 5: 36.6 – 36.69 MbChr 15: 8.66 – 8.74 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

EAAT1 is predominantly expressed in the plasma membrane, allowing it to remove glutamate from the extracellular space.[6] It has also been localized in the inner mitochondrial membrane as part of the malate-aspartate shuttle.[7]

Mechanism

EAAT1 functions in vivo as a homotrimer.[8] EAAT1 mediates the transport of glutamic and aspartic acid with the cotransport of three Na+ and one H+ cations and counter transport of one K+ cation. This co-transport coupling (or symport) allows the transport of glutamate into cells against a concentration gradient.[9]

  • "Diagram Illustrating the Malate-Aspartate Shuttle Pathway". (Glutamate aspartate transporter labeled at bottom center.)
    "Diagram Illustrating the Malate-Aspartate Shuttle Pathway". (Glutamate aspartate transporter labeled at bottom center.)
  • Expression of SLC1A3 in the Bergmann glia fibers. Mouse brain at 7th postnatal day, sagittal section; GENSAT database.
    Expression of SLC1A3 in the Bergmann glia fibers. Mouse brain at 7th postnatal day, sagittal section; GENSAT database.

Tissue distribution

EAAT1 is expressed throughout the CNS,[10] and is highly expressed in astrocytes and Bergmann glia in the cerebellum.[11][12] In the retina, EAAT1 is expressed in Muller cells.[13] EAAT1 is also expressed in a number of other tissues including cardiac myocytes.[7]

Clinical significance

It is associated with type 6 episodic ataxia.[14] EAAT1 expression may also be associated with osteoarthritis.[15]

Pharmacology

DL-threo-beta-benzyloxyaspartate (TBOA) is an inhibitor of the excitatory amino acid transporters.[16]

Selective inhibitors for EAAT1 have recently been discovered based on 25 combinations of substitutions at the 4 and 7 positions of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitril.[17]

References
  1. GRCh38: Ensembl release 89: ENSG00000079215 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000005360 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: SLC1A3 solute carrier family 1 (glial high affinity glutamate transporter), member 3".
  6. Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC (March 1995). "Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations". The Journal of Neuroscience. 15 (3 Pt 1): 1835–53. doi:10.1523/JNEUROSCI.15-03-01835.1995. PMC 6578153. PMID 7891138.
  7. Ralphe JC, Segar JL, Schutte BC, Scholz TD (July 2004). "Localization and function of the brain excitatory amino acid transporter type 1 in cardiac mitochondria". Journal of Molecular and Cellular Cardiology. 37 (1): 33–41. doi:10.1016/j.yjmcc.2004.04.008. PMID 15242733.
  8. Gendreau S, Voswinkel S, Torres-Salazar D, Lang N, Heidtmann H, Detro-Dassen S, Schmalzing G, Hidalgo P, Fahlke C (September 2004). "A trimeric quaternary structure is conserved in bacterial and human glutamate transporters". The Journal of Biological Chemistry. 279 (38): 39505–12. doi:10.1074/jbc.M408038200. PMID 15265858. S2CID 16077315.
  9. Kanai Y, Hediger MA (February 2004). "The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects". Pflügers Archiv. 447 (5): 469–79. doi:10.1007/s00424-003-1146-4. PMID 14530974. S2CID 21564906.
  10. Danbolt NC (September 2001). "Glutamate uptake". Progress in Neurobiology. 65 (1): 1–105. doi:10.1016/S0301-0082(00)00067-8. PMID 11369436. S2CID 27347413.
  11. Storck T, Schulte S, Hofmann K, Stoffel W (November 1992). "Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain". Proceedings of the National Academy of Sciences of the United States of America. 89 (22): 10955–9. Bibcode:1992PNAS...8910955S. doi:10.1073/pnas.89.22.10955. PMC 50461. PMID 1279699.
  12. Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D, Nash N, Kuncl RW (September 1994). "Localization of neuronal and glial glutamate transporters". Neuron. 13 (3): 713–25. doi:10.1016/0896-6273(94)90038-8. PMID 7917301. S2CID 45299639.
  13. Rauen T, Taylor WR, Kuhlbrodt K, Wiessner M (January 1998). "High-affinity glutamate transporters in the rat retina: a major role of the glial glutamate transporter GLAST-1 in transmitter clearance". Cell and Tissue Research. 291 (1): 19–31. doi:10.1007/s004410050976. PMID 9394040. S2CID 6814592.
  14. Jen JC, Wan J, Palos TP, Howard BD, Baloh RW (August 2005). "Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures". Neurology. 65 (4): 529–34. doi:10.1212/01.WNL.0000172638.58172.5a. PMID 16116111. S2CID 22492395.
  15. Mason DJ, Brakspear K, Wilson C, Williams R, Kotwal RS (July 2010). "Expression of glutamate receptors and transporters in human subchondral bone in osteoarthritis". Orthopaedic Proceedings. The British Editorial Society of Bone & Joint Surgery. 93-B (SUPP_I): 411. doi:10.1302/0301-620X.93BSUPP_I.0930069b (inactive 1 August 2023).{{cite journal}}: CS1 maint: DOI inactive as of August 2023 (link)
  16. Shimamoto K, Lebrun B, Yasuda-Kamatani Y, Sakaitani M, Shigeri Y, Yumoto N, Nakajima T (February 1998). "DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters". Molecular Pharmacology. 53 (2): 195–201. doi:10.1124/mol.53.2.195. PMID 9463476.
  17. Jensen AA, Erichsen MN, Nielsen CW, Stensbøl TB, Kehler J, Bunch L (February 2009). "Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1". Journal of Medicinal Chemistry. 52 (4): 912–5. doi:10.1021/jm8013458. PMID 19161278.

Further reading
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