Excitatory amino acid transporter 1

Last updated
SLC1A3
Identifiers
Aliases SLC1A3 , EA6, EAAT1, GLAST, GLAST1, solute carrier family 1 member 3
External IDs OMIM: 600111 MGI: 99917 HomoloGene: 20882 GeneCards: SLC1A3
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001166695
NM_001166696
NM_001289939
NM_001289940
NM_004172

Contents

NM_148938

RefSeq (protein)

NP_001160167
NP_001160168
NP_001276868
NP_001276869
NP_004163

NP_683740

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

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).

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]

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]

Related Research Articles

<span class="mw-page-title-main">Glutamic acid</span> Amino acid and neurotransmitter

Glutamic acid is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synthesize enough for its use. It is also the most abundant excitatory neurotransmitter in the vertebrate nervous system. It serves as the precursor for the synthesis of the inhibitory gamma-aminobutyric acid (GABA) in GABAergic neurons.

<span class="mw-page-title-main">Glutamate receptor</span> Cell-surface proteins that bind glutamate and trigger changes which influence the behavior of cells

Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

Glutamate transporters are a family of neurotransmitter transporter proteins that move glutamate – the principal excitatory neurotransmitter – across a membrane. The family of glutamate transporters is composed of two primary subclasses: the excitatory amino acid transporter (EAAT) family and vesicular glutamate transporter (VGLUT) family. In the brain, EAATs remove glutamate from the synaptic cleft and extrasynaptic sites via glutamate reuptake into glial cells and neurons, while VGLUTs move glutamate from the cell cytoplasm into synaptic vesicles. Glutamate transporters also transport aspartate and are present in virtually all peripheral tissues, including the heart, liver, testes, and bone. They exhibit stereoselectivity for L-glutamate but transport both L-aspartate and D-aspartate.

<span class="mw-page-title-main">Excitatory amino acid transporter 4</span> Protein found in humans

Excitatory amino-acid transporter 4 (EAAT4) is a protein that in humans is encoded by the SLC1A6 gene.

<i>N</i>-Acetylaspartic acid Derivative of aspartic acid found in the brain

N-Acetylaspartic acid, or N-acetylaspartate (NAA), is a derivative of aspartic acid with a formula of C6H9NO5 and a molecular weight of 175.139.

Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations. There are more than twenty types of neurotransmitter transporters.

<span class="mw-page-title-main">GRIN2A</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit epsilon-1 is a protein that in humans is encoded by the GRIN2A gene. With 1464 amino acids, the canonical GluN2A subunit isoform is large. GluN2A-short isoforms specific to primates can be produced by alternative splicing and contain 1281 amino acids.

A neurotransmitter sodium symporter (NSS) (TC# 2.A.22) is type of neurotransmitter transporter that catalyzes the uptake of a variety of neurotransmitters, amino acids, osmolytes and related nitrogenous substances by a solute:Na+ symport mechanism. The NSS family is a member of the APC superfamily. Its constituents have been found in bacteria, archaea and eukaryotes.

<span class="mw-page-title-main">GRIN1</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit zeta-1 is a protein that in humans is encoded by the GRIN1 gene.

<span class="mw-page-title-main">GRIA1</span> Mammalian protein found in Homo sapiens

Glutamate receptor 1 is a protein that in humans is encoded by the GRIA1 gene.

<span class="mw-page-title-main">Excitatory amino acid transporter 2</span> Protein found in humans

Excitatory amino acid transporter 2 (EAAT2) also known as solute carrier family 1 member 2 (SLC1A2) and glutamate transporter 1 (GLT-1) is a protein that in humans is encoded by the SLC1A2 gene. Alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.

<span class="mw-page-title-main">Excitatory amino acid transporter 3</span> Protein found in humans

Excitatory amino acid transporter 3 (EAAT3), is a protein that in humans is encoded by the SLC1A1 gene.

<span class="mw-page-title-main">Neutral amino acid transporter B(0)</span> Protein-coding gene in the species Homo sapiens

Neutral amino acid transporter B(0) is a protein that in humans is encoded by the SLC1A5 gene.

<span class="mw-page-title-main">GRIN3A</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit 3A is a protein that in humans is encoded by the GRIN3A gene.

<span class="mw-page-title-main">GRIN2D</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit epsilon-4 is a protein that in humans is encoded by the GRIN2D gene.

<span class="mw-page-title-main">Cystine/glutamate transporter</span> Protein found in humans

Cystine/glutamate transporter is an antiporter that in humans is encoded by the SLC7A11 gene.

In biochemistry, the glutamate–glutamine cycle is a cyclic metabolic pathway which maintains an adequate supply of the neurotransmitter glutamate in the central nervous system. Neurons are unable to synthesize either the excitatory neurotransmitter glutamate, or the inhibitory GABA from glucose. Discoveries of glutamate and glutamine pools within intercellular compartments led to suggestions of the glutamate–glutamine cycle working between neurons and astrocytes. The glutamate/GABA–glutamine cycle is a metabolic pathway that describes the release of either glutamate or GABA from neurons which is then taken up into astrocytes. In return, astrocytes release glutamine to be taken up into neurons for use as a precursor to the synthesis of either glutamate or GABA.

Dicarboxylic aminoaciduria is a rare form of aminoaciduria which is an autosomal recessive disorder of urinary glutamate and aspartate due to genetic errors related to transport of these amino acids. Mutations resulting in a lack of expression of the SLC1A1 gene, a member of the solute carrier family, are found to cause development of dicarboxylic aminoaciduria in humans. SLC1A1 encodes for EAAT3 which is found in the neurons, intestine, kidney, lung, and heart. EAAT3 is part of a family of high affinity glutamate transporters which transport both glutamate and aspartate across the plasma membrane.

An excitatory amino acid reuptake inhibitor (EAARI) is a type of drug which inhibits the reuptake of the excitatory neurotransmitters glutamate and aspartate by blocking one or more of the excitatory amino acid transporters (EAATs).

<span class="mw-page-title-main">Glutamate (neurotransmitter)</span> Anion of glutamic acid in its role as a neurotransmitter

In neuroscience, glutamate is the anion of glutamic acid in its role as a neurotransmitter. It is by a wide margin the most abundant excitatory neurotransmitter in the vertebrate nervous system. It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000079215 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 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 31 January 2024).{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (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