Biology:Excitatory amino acid transporter 1
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Short description: Protein found in humans
 Generic protein structure example |
Excitatory amino acid transporter 1 (EAAT1) is a protein that, in humans, is encoded by the SLC1A3 gene.[1] EAAT1 is also often called the GLutamate ASpartate Transporter 1 (GLAST-1).
EAAT1 is predominantly expressed in the plasma membrane, allowing it to remove glutamate from the extracellular space.[2] It has also been localized in the inner mitochondrial membrane as part of the malate-aspartate shuttle.[3]
Mechanism
EAAT1 functions in vivo as a homotrimer.[4] 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.[5]
"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.
Tissue distribution
EAAT1 is expressed throughout the CNS,[6] and is highly expressed in astrocytes and Bergmann glia in the cerebellum.[7][8] In the retina, EAAT1 is expressed in Muller cells.[9] EAAT1 is also expressed in a number of other tissues including cardiac myocytes.[3]
Clinical significance
It is associated with type 6 episodic ataxia.[10] EAAT1 expression may also be associated with osteoarthritis.[11]
Pharmacology
DL-threo-beta-benzyloxyaspartate (TBOA) is an inhibitor of the excitatory amino acid transporters.[12]
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.[13]
References
- ↑ "Entrez Gene: SLC1A3 solute carrier family 1 (glial high affinity glutamate transporter), member 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6507.
- ↑ "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. March 1995. doi:10.1523/JNEUROSCI.15-03-01835.1995. PMID 7891138.
- ↑ 3.0 3.1 "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. July 2004. doi:10.1016/j.yjmcc.2004.04.008. PMID 15242733.
- ↑ "A trimeric quaternary structure is conserved in bacterial and human glutamate transporters". The Journal of Biological Chemistry 279 (38): 39505–12. September 2004. doi:10.1074/jbc.M408038200. PMID 15265858.
- ↑ "The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects". Pflügers Archiv 447 (5): 469–79. February 2004. doi:10.1007/s00424-003-1146-4. PMID 14530974.
- ↑ "Glutamate uptake". Progress in Neurobiology 65 (1): 1–105. September 2001. doi:10.1016/S0301-0082(00)00067-8. PMID 11369436.
- ↑ "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. November 1992. doi:10.1073/pnas.89.22.10955. PMID 1279699. Bibcode: 1992PNAS...8910955S.
- ↑ "Localization of neuronal and glial glutamate transporters". Neuron 13 (3): 713–25. September 1994. doi:10.1016/0896-6273(94)90038-8. PMID 7917301.
- ↑ "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. January 1998. doi:10.1007/s004410050976. PMID 9394040.
- ↑ "Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures". Neurology 65 (4): 529–34. August 2005. doi:10.1212/01.WNL.0000172638.58172.5a. PMID 16116111.
- ↑ "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. July 2010. doi:10.1302/0301-620X.93BSUPP_I.0930069b. https://online.boneandjoint.org.uk/doi/abs/10.1302/0301-620X.93BSUPP_I.0930069b.
- ↑ "DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters". Molecular Pharmacology 53 (2): 195–201. February 1998. doi:10.1124/mol.53.2.195. PMID 9463476.
- ↑ "Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1". Journal of Medicinal Chemistry 52 (4): 912–5. February 2009. doi:10.1021/jm8013458. PMID 19161278.
Further reading
- "Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex". The Journal of Neuroscience 14 (9): 5559–69. September 1994. doi:10.1523/jneurosci.14-09-05559.1994. PMID 7521911.
- "Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1". DNA Research 1 (5): 223–9. 1995. doi:10.1093/dnares/1.5.223. PMID 7584044.
- "Localization of the gene (SLC1A3) encoding human glutamate transporter (GluT-1) to 5p13 by fluorescence in situ hybridization". Cytogenetics and Cell Genetics 69 (3–4): 209–10. 1995. doi:10.1159/000133965. PMID 7698014.
- "Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain". Brain Research 662 (1–2): 245–50. October 1994. doi:10.1016/0006-8993(94)90819-2. PMID 7859077.
- "The mouse and human excitatory amino acid transporter gene (EAAT1) maps to mouse chromosome 15 and a region of syntenic homology on human chromosome 5". Genomics 22 (3): 631–3. August 1994. doi:10.1006/geno.1994.1437. PMID 8001975.
- "Cloning and expression of a human glutamate transporter". Biochemical and Biophysical Research Communications 199 (1): 171–6. February 1994. doi:10.1006/bbrc.1994.1210. PMID 8123008.
- "Cloning and characterization of a glutamate transporter cDNA from human cerebellum". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1216 (1): 161–4. October 1993. doi:10.1016/0167-4781(93)90057-K. PMID 8218410.
- "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry 236 (1): 107–13. April 1996. doi:10.1006/abio.1996.0138. PMID 8619474.
- "Human high affinity, Na(+)-dependent L-glutamate/L-aspartate transporter GLAST-1 (EAAT-1): gene structure and localization to chromosome 5p11-p12". FEBS Letters 386 (2–3): 189–93. May 1996. doi:10.1016/0014-5793(96)00424-3. PMID 8647279.
- "Large-scale concatenation cDNA sequencing". Genome Research 7 (4): 353–8. April 1997. doi:10.1101/gr.7.4.353. PMID 9110174.
- "Properties of excitatory amino acid transport in the human U373 astrocytoma cell line". Brain Research 839 (2): 235–42. August 1999. doi:10.1016/S0006-8993(99)01714-X. PMID 10519046.
- "Differentiation of substrate and nonsubstrate inhibitors of the high-affinity, sodium-dependent glutamate transporters". Molecular Pharmacology 56 (6): 1095–104. December 1999. doi:10.1124/mol.56.6.1095. PMID 10570036.
- "Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange". The Journal of Neuroscience 19 (24): 10767–77. December 1999. doi:10.1523/jneurosci.19-24-10767.1999. PMID 10594060.
- "Human T-cell lymphotropic virus type 1-infected T lymphocytes impair catabolism and uptake of glutamate by astrocytes via Tax-1 and tumor necrosis factor alpha". Journal of Virology 74 (14): 6433–41. July 2000. doi:10.1128/JVI.74.14.6433-6441.2000. PMID 10864655.
- "EAAT1 is involved in transport of L-glutamate during differentiation of the Caco-2 cell line". American Journal of Physiology. Gastrointestinal and Liver Physiology 279 (2): G366-73. August 2000. doi:10.1152/ajpgi.2000.279.2.G366. PMID 10915646.
- "Sulfhydryl modification of V449C in the glutamate transporter EAAT1 abolishes substrate transport but not the substrate-gated anion conductance". Proceedings of the National Academy of Sciences of the United States of America 98 (26): 15324–9. December 2001. doi:10.1073/pnas.011400198. PMID 11752470. Bibcode: 2001PNAS...9815324S.
- "Benzodiazepines differently modulate EAAT1/GLAST and EAAT2/GLT1 glutamate transporters expressed in CHO cells". Neurochemistry International 40 (4): 321–6. April 2002. doi:10.1016/S0197-0186(01)00087-0. PMID 11792462.
- "Aberrant expression of the glutamate transporter excitatory amino acid transporter 1 (EAAT1) in Alzheimer's disease". The Journal of Neuroscience 22 (3): RC206. February 2002. doi:10.1523/jneurosci.22-03-j0004.2002. PMID 11826152.
- "Expression of excitatory amino acid transporter-1 in brain macrophages and microglia of HIV-infected patients. A neuroprotective role for activated microglia?". Journal of Neuropathology and Experimental Neurology 62 (5): 475–85. May 2003. doi:10.1093/jnen/62.5.475. PMID 12769187.
External links
- Glutamate+Aspartate+Transporter+1 at the US National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P43003 (Excitatory amino acid transporter 1) at the PDBe-KB.
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