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Excitatory amino-acid transporters (EAATs), also known as glutamate transporters, belong to the family of neurotransmitter transporters. Glutamate is the principal excitatory neurotransmitter in the vertebrate brain. EAATs serve to terminate the excitatory signal by removal (uptake) of glutamate from the neuronal synapse into neuroglia and neurons.

The EAATs are membrane-bound secondary transporters that superficially resemble ion channels.^[1] These transporters play the important role of regulating concentrations of glutamate in the extracellular space by transporting it along with other ions across cellular membranes.^[2] After glutamate is released as the result of an action potential, glutamate transporters quickly remove it from the extracellular space to keep its levels low, thereby terminating the synaptic transmission.^[1]^[3]

Without the activity of glutamate transporters, glutamate would build up and kill cells in a process called excitotoxicity, in which excessive amounts of glutamate acts as a toxin to neurons by triggering a number of biochemical cascades. The activity of glutamate transporters also allows glutamate to be recycled for repeated release.^[4]

Glutamate transporters also transport aspartate and are present in virtually all peripheral tissues including bone, heart, liver, and testes. They exhibit stereoselectivity for L-glutamate but transport both L- and D-aspartate.

Classes[edit]

There are two general classes of glutamate transporters, those that are dependent on an electrochemical gradient of sodium ions (the EAATs) and those that are not (VGLUTs and xCT).^[5] The cystine-glutamate antiporter (xCT) is localised to the plasma membrane of cells whilst vesicular glutamate transporters (VGLUTs) are found in the membrane of glutamate-containing synaptic vesicles. Na⁺-dependent EAATs are also dependent on transmembrane K⁺ and H⁺concentration gradients, and so are also known as 'sodium and potassium coupled glutamate transporters'. Na⁺-dependent transporters have also been called 'high-affinity glutamate transporters', though their glutamate affinity actually varies widely.^[5]

Mitochondria also possess mechanisms for taking up glutamate that are quite distinct from membrane glutamate transporters.^[5]

EAATs[edit]

In humans (as well as in rodents), five subtypes have been identified and named EAAT1-5 (SLC1A3, SLC1A2, SLC1A1, SLC1A6, SLC1A7). Subtypes EAAT1-2 are found in membranes of glial cells (astrocytes, microglia, and oligodendrocytes) as well as in endothelial cells, whereas subtypes EAAT3-4 are located on neurons.^[6] Finally, EAAT5 is only found in the retina where it is principally localised to photoreceptors and bipolar neurons in the retina.^[7] In rodents, the orthologs for EAAT1-3 are named GLAST, GLT1, and EAAC1, respectively,^[3] whereas the acronyms EAAT4 and EAAT5 are conserved.

When glutamate is taken up into glial cells by the EAATs, it is converted to glutamine and subsequently transported back into the presynaptic neuron, converted back into glutamate, and taken up into synaptic vesicles by action of the VGLUTs.^[3]^[8] This process is named the glutamate-glutamine cycle.

The glial transporters - in particular the various splice variants of GLT-1 (EAAT2) - play the largest role (90%) in regulating extracellular glutamate concentration.^[9]

protein	gene	tissue distribution
EAAT1	SLC1A3	glial and endothelial cells
EAAT2	SLC1A2	glial and endothelial cells
EAAT3	SLC1A1	neurons
EAAT4	SLC1A6	neurons
EAAT5	SLC1A7	retina
VGLUT1	SLC17A7	neurons
VGLUT2	SLC17A6	neurons
VGLUT3	SLC17A8	neurons

VGLUTs[edit]

Four types of vesicular glutamate transporters are known, VGLUTs 1–3^[10] (SLC17A7, SLC17A6, and SLC17A8 respectively)^[3] and the novel glutamate/aspartate transporter sialin.^[11] These transporters pack the neurotransmitter into synaptic vesicles so that they can be released into the synapse. VGLUTs are dependent on the proton gradient that exists in the secretory system (vesicles being more acidic than the cytosol). VGLUTs have only between one hundredth and one thousandth the affinity for glutamate that EAATs have.^[3] Also unlike EAATs, they do not appear to transport aspartate.

Pathology[edit]

Overactivity of glutamate transporters may result in inadequate synaptic glutamate and may be involved in schizophrenia and other mental illnesses.^[1]

During injury processes such as ischemia and traumatic brain injury, the action of glutamate transporters may fail, leading to toxic buildup of glutamate. In fact, their activity may also actually be reversed due to inadequate amounts of adenosine triphosphate to power ATPase pumps, resulting in the loss of the electrochemical ion gradient. Since the direction of glutamate transport depends on the ion gradient, these transporters release glutamate instead of removing it, which results in neurotoxicity due to overactivation of glutamate receptors.^[12]

Loss of the Na⁺-dependent glutamate transporter EAAT2 is suspected to be associated with neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and ALS–parkinsonism dementia complex.^[13] Also, degeneration of motor neurons in the disease amyotrophic lateral sclerosis has been linked to loss of EAAT2 from patients' brains and spinal cords.^[13]

References[edit]

^ ^a ^b ^c Ganel R, Rothstein JD (1999). "Chapter 15, Glutamate transporter dysfunction and neuronal death". In Monyer, Hannah; Gabriel A. Adelmann; Jonas, Peter. Ionotropic glutamate receptors in the CNS. Berlin: Springer. pp. 472–493. ISBN 3-540-66120-4.
^ Zerangue, N, Kavanaugh, MP (1996). "Flux coupling in a neuronal glutamate transporter". Nature 383 (6601): 634–37. doi:10.1038/383634a0. PMID 8857541.
^ ^a ^b ^c ^d ^e Shigeri Y, Seal RP, Shimamoto K (2004). "Molecular pharmacology of glutamate transporters, EAATs and VGLUTs". Brain Res. Brain Res. Rev. 45 (3): 250–65. doi:10.1016/j.brainresrev.2004.04.004. PMID 15210307.
^ Zou JY, Crews FT (2005). "TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition". Brain Res. 1034 (1-2): 11–24. doi:10.1016/j.brainres.2004.11.014. PMID 15713255.
^ ^a ^b ^c Danbolt NC (2001). "Glutamate uptake". Prog. Neurobiol. 65 (1): 1–105. doi:10.1016/S0301-0082(00)00067-8. PMID 11369436.
^ Anderson CM, Swanson RA (2000). "Astrocyte glutamate transport: review of properties, regulation, and physiological functions". Glia 32 (1): 1–14. doi:10.1002/1098-1136(200010)32:1. PMID 10975906.
^ Pow DV, Barnett NL (2000). "Developmental expression of excitatory amino acid transporter 5: a photoreceptor and bipolar cell glutamate transporter in rat retina". Neurosci. Lett. 280 (1): 21–4. doi:10.1016/S0304-3940(99)00988-X. PMID 10696802.
^ Pow DV, Robinson SR (1994). "Glutamate in some retinal neurons is derived solely from glia". Neuroscience 60 (2): 355–66. doi:10.1016/0306-4522(94)90249-6. PMID 7915410.
^ Shachnai L, Shimamoto K, Kanner BI (2005). "Sulfhydryl modification of cysteine mutants of a neuronal glutamate transporter reveals an inverse relationship between sodium dependent conformational changes and the glutamate-gated anion conductance". Neuropharmacology 49 (6): 862–71. doi:10.1016/j.neuropharm.2005.07.005. PMID 16137722.
^ Naito S, Ueda T (January 1983). "Adenosine triphosphate-dependent uptake of glutamate into protein I-associated synaptic vesicles". J. Biol. Chem. 258 (2): 696–9. PMID 6130088.
^ Miyaji T, Echigo N, Hiasa M, Senoh S, Omote H, Moriyama Y (August 2008). "Identification of a vesicular aspartate transporter". Proc. Natl. Acad. Sci. U.S.A. 105 (33): 11720–4. doi:10.1073/pnas.0804015105. PMC 2575331. PMID 18695252.
^ Kim AH, Kerchner GA, Choi DW (2002). "Chapter 1, Blocking Excitotoxicity". In Marcoux, Frank W. CNS neuroprotection. Berlin: Springer. pp. 3–36. ISBN 3-540-42412-1.
^ ^a ^b Yi JH, Hazell AS (2006). "Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury". Neurochem. Int. 48 (5): 394–403. doi:10.1016/j.neuint.2005.12.001. PMID 16473439.

External links[edit]

Glutamate Transporter at the US National Library of Medicine Medical Subject Headings (MeSH)

English Journal

Glutamate release from platelets: Exocytosis versus glutamate transporter reversal.

Kasatkina LA, Borisova TA.SourceDepartment of Neurochemistry, Palladin Institute of Biochemistry, NAS of Ukraine, 9 Leontovicha Street, Kyiv 01601, Ukraine. Electronic address: ludmilka.kasatkina@gmail.com.
The international journal of biochemistry & cell biology.Int J Biochem Cell Biol.2013 Nov;45(11):2585-95. doi: 10.1016/j.biocel.2013.08.004. Epub 2013 Aug 30.
Platelets express neuronal and glial glutamate transporters EAAT 1-3 in the plasma membrane and vesicular glutamate transporters VGLUT 1,2 in the membrane of secretory granules. This study is focused on the assessment of non-exocytotic glutamate release, that is, the unstimulated release, heteroexch
PMID 23994539

Mechanism of transport modulation by an extracellular loop in an archaeal Excitatory Amino Acid Transporter (EAAT) homolog.

Mulligan C, Mindell JA.SourceNINDS/NIH, United States.
The Journal of biological chemistry.J Biol Chem.2013 Oct 23. [Epub ahead of print]
Secondary transporters in the excitatory amino acid transporters (EAATs) family terminate glutamatergic synaptic transmission by catalyzing Na+-dependent removal of glutamate from the synaptic cleft. Recent structural studies of the aspartate-specific, archaeal homolog, GltPh, suggest that transport
PMID 24155238

Glutamate dysregulation in the trigeminal ganglion: A novel mechanism forperipheral sensitization of the craniofacial region.

Laursen JC, Cairns BE, Dong XD, Kumar U, Somvanshi RK, Arendt-Nielsen L, Gazerani P.SourceCenter for Sensory-Motor Interaction, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Fredrik Bajers Vej 7D3, DK-9220,Aalborg East, Denmark.
Neuroscience.Neuroscience.2013 Oct 18. pii: S0306-4522(13)00853-1. doi: 10.1016/j.neuroscience.2013.10.009. [Epub ahead of print]
In the trigeminal ganglion, satellite glial cells (SGCs) form a functional unit with neurons. It has been proposed that SGCs participate in regulating extracellular glutamate levels and that dysfunction of this SGC capacity can impact nociceptive transmission in craniofacial pain conditions. This st
PMID 24144624

Japanese Journal

ロテノンに対する生体防御反応としてのグルタミン酸トランスポーターEAAT3の分解抑制

山本智美,足立暁,古武弥一郎,太田茂
日本毒性学会学術年会 40.1(0), 2003193, 2013
… 脳におけるグルタミン酸の調節にはグルタミン酸トランスポーター (excitatory amino acid transporter:EAAT)が関与しており，EAAT5つのサブタイプのうち神経細胞に主に発現しているのはEAAT3である。 …
NAID 130004676786

Niflumic Acid Activates Additional Currents of the Human Glial L-Glutamate Transporter EAAT1 in a Substrate-Dependent Manner

Takahashi Kanako,Ishii-Nozawa Reiko,Takeuchi Koichi [他],Nakazawa Ken,Sekino Yuko,Sato Kaoru
Biological and Pharmaceutical Bulletin 36(12), 1996-2004, 2013
… The astrocytic L-glutamate (L-Glu) transporter EAAT1 participates in the removal of L-Glu from the synaptic cleft and maintenance of non-toxic concentrations in the extracellular fluid. …
NAID 130003382068

Ca(v)2.1 in Cerebellar Purkinje Cells Regulates Competitive Excitatory Synaptic Wiring, Cell Survival, and Cerebellar Biochemical Compartmentalization

Miyazaki Taisuke,Yamasaki Miwako,Hashimoto Kouichi,Yamazaki Maya,Abe Manabu,Usui Hiroshi,Kano Masanobu,Sakimura Kenji,Watanabe Masahiko
JOURNAL OF NEUROSCIENCE 32(4), 1311-1328, 2012-01-25
… A similar alteration was noted in the banded expression of the glutamate transporter EAAT4 in PC-Cav2.1 KO mice. …
NAID 120005208889

Related Pictures

DELETED DXCC - 21 : 10 : 1990 Beifahrersitz-Stoff-Elektra-Anthrazit-EAAT EAAT RENNES: insigne de l'escadrille Box 2 | Astrocyte–neuron interactions at The Star of the East Diamond Private I-EAAT aircraft at Trento Thread: TBM700N_EAAT.zip

★リンクテーブル★

リンク元	「興奮性アミノ酸トランスポーター」「excitatory amino acid transporter」「興奮性アミノ酸輸送体」
拡張検索	「EAAT2」「EAAT3」「EAAT4」「EAAT5」「EAAT1」
関連記事	「EAA」「EA」