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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/07/29 11:02:53」(JST)

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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

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

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 EAAT3-4 is 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

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

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

^ ^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. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2575331.
^ 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

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

English Journal

Epileptiform activity and behavioral arrests in mice overexpressing the calcium channel subunit α2δ-1.

Faria LC1, Gu F1, Parada I1, Barres B2, Luo ZD3, Prince DA4.
Neurobiology of disease.Neurobiol Dis.2017 Jun;102:70-80. doi: 10.1016/j.nbd.2017.01.009. Epub 2017 Feb 11.
PMID 28193459

Function and expression of a splicing variant of vesicular glutamate transporter 1.

Moriyama S1, Iharada M1, Omote H1, Moriyama Y2, Hiasa M3.
Biochimica et biophysica acta.Biochim Biophys Acta.2017 May;1859(5):931-940. doi: 10.1016/j.bbamem.2017.02.002. Epub 2017 Feb 8.
PMID 28188742

dl-3-n-butylphthalide promotes neuroplasticity and motor recovery in stroke rats.

Sun Y1, Cheng X2, Wang H2, Mu X2, Liang Y2, Luo Y2, Qu H3, Zhao C4.
Behavioural brain research.Behav Brain Res.2017 Apr 22;329:67-74. doi: 10.1016/j.bbr.2017.04.039. [Epub ahead of print]
PMID 28442357

Japanese Journal

SiN多孔膜を有するマイクロウェルを用いた単一ニューロンの長期培養

善明祐介,森迫勇,安田隆
電気学会論文誌. E, センサ・マイクロマシン部門誌 138(7), 327-328, 2018
… By fluorescently staining VGLUT1 (vesicular glutamate transporter 1) which is localized at a presynaptic terminal, we found that the number of synapses formed by a single neuron drastically increases within the first 2 weeks and keeps high values for weeks afterward.</p> …
NAID 130007386996

The effects of unilateral cochlear ablation on the expression of vesicular glutamate transporter 1 in the lower auditory pathway of neonatal rats

Hasegawa Hiroki,Hatano Miyako,Sugimoto Hisashi,Ito Makoto,Kawasaki Hiroshi,Yoshizaki Tomokazu
Auris Nasus Larynx 44(6), 690-699, 2017-12-01
… Methods: We examined the effects of unilateral cochlear ablation on VGLUT1 expression in the cochlear nucleus (CN) and the superior olivary complex (SOC) in neonatal rats. … Results: VGLUT1 expression in the CN subdivisions (the AVCN, the PVCN and the DCN-deep layers) and the SOC (the MnTB, the LSO and the MSO) ipsilateral to the ablated side was significantly suppressed by unilateral cochlear ablation. …
NAID 120006027764

Essential roles of aspartate aminotransferase 1 and vesicular glutamate transporters in β-cell glutamate signaling for incretin-induced insulin secretion

Murao Naoya,Yokoi Norihide,Honda Kohei,Han Guirong,Hayami Tomohide,Gheni Ghupurjan,Takahashi Harumi,Minami Kohtaro,Seino Susumu
PLoS ONE 12(11), e0187213, 2017-11-01
… To directly prove the model, we have established and characterized CRISPR/Cas9-engineered clonal mouse β-cell lines deficient for the genes critical in these two processes: aspartate aminotransferase 1 (AST1, gene symbol Got1), a key enzyme in the MA shuttle, which generates cytosolic glutamate, and the vesicular glutamate transporters (VGLUT1, VGLUT2, and VGLUT3, gene symbol Slc17a7, Slc17a6, and Slc17a8, respectively), which participate in glutamate transport into secretory vesicles. …
NAID 120006373802

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