EAAT1
EAAT1（excitatory amino acid transporter 1）、SLC1A3（solute carrier family 1 member 3）またはGLAST1（glutamate/aspartate transporter 1）は、ヒトではSLC1A3遺伝子にコードされるタンパク質である[5]。
EAAT1は主に細胞膜に発現しており、細胞外空間のグルタミン酸の除去を可能にする[6]。また、リンゴ酸-アスパラギン酸シャトルの構成因子として、ミトコンドリア内膜にも局在している[7]。
機構
[編集]EAAT1はin vivoではホモ三量体として機能する[8]。EAAT1は、3つのNa+と1つのH+との共輸送、1つのK+との逆輸送によって、グルタミン酸とアスパラギン酸の輸送を媒介する。こうした輸送の共役（シンポート）によって、グルタミン酸を濃度勾配に逆らって細胞内へ輸送することが可能となる[9]。
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リンゴ酸-アスパラギン酸シャトルの模式図。グルタミン酸/アスパラギン酸トランスポーターは下部中央に示されている。 -
バーグマングリア線維におけるSLC1A3の発現。出生後7日マウス脳、矢状断、GENSATデータベース。
組織分布
[編集]EAAT1は中枢神経系全体に発現しており[10]、小脳のアストロサイトやバーグマングリアで高度に発現している[11][12]。網膜においては、EAAT1はミュラー細胞に発現している[13]。EAAT1は、心筋細胞など他のいくつかの組織でも発現している[7]。
臨床的意義
[編集]EAAT1は周期性失調症6型（EA6）と関係している[14]。EAAT1の発現は、変形性関節症と関係している可能性もある[15]。
薬理
[編集]TBOA（DL-threo-beta-benzyloxyaspartate）は、興奮性アミノ酸トランスポーター（EAAT）の阻害剤である[16]。
2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrilの4位と7位を置換した25種類の化合物による検討から、EAAT1選択性を示す阻害剤が発見されている[17]。
出典
[編集]- ^ a b c GRCh38: Ensembl release 89: ENSG00000079215 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000005360 - Ensembl, May 2017
- ^ Human PubMed Reference:
- ^ Mouse PubMed Reference:
- ^ “Entrez Gene: SLC1A3 solute carrier family 1 (glial high affinity glutamate transporter), member 3”. 2023年5月7日閲覧。
- ^ “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. PMC 6578153. PMID 7891138.
- ^ a b “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). Bibcode: 1992PNAS...8910955S. doi:10.1073/pnas.89.22.10955. PMC 50461. PMID 1279699.
- ^ “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.
- ^ “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.
関連文献
[編集]- “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. PMC 6577102. 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. PMC 139146. 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. PMC 6784962. 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. PMC 112151. 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). Bibcode: 2001PNAS...9815324S. doi:10.1073/pnas.011400198. PMC 65028. PMID 11752470.
- “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. PMC 6758536. 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.
外部リンク
[編集]- Glutamate Aspartate Transporter 1 - MeSH・アメリカ国立医学図書館・生命科学用語シソーラス
- Overview of all the structural information available in the PDB for UniProt: P43003 (Excitatory amino acid transporter 1) at the PDBe-KB.