Document Information

PMID 9745361  (  )
Title Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration?
Abstract Increasing evidence indicates that glutamate transporters are vulnerable to the action of biological oxidants, resulting in reduced uptake function. This effect could contribute to the build-up of neurotoxic extracellular glutamate levels, with major pathological consequences. Specific 'redox-sensing' elements, consisting of cysteine residues, have been identified in the structures of at least three transporter subtypes (GLT1, GLAST and EAAC1) and shown to regulate transport rate via thiol-disulphide redox interconversion. In this article, Davide Trotti, Niels Danbolt and Andrea Volterra discuss these findings in relation to the emerging view that in brain diseases oxidative and excitotoxic mechanisms might often operate in tight conjunction to induce neuronal damage. In particular, they review evidence suggesting a possible involvement of oxidative alterations of glutamate transporters in specific pathologies, including amyotrophic lateral sclerosis, Alzheimer's disease, brain trauma and ischaemia. School, Boston, MA 02115, USA.

NOTE: Color highlight is limited to the abstract and SciMiner text-mining mode. If you see much more identified targets below from "Targets by SciMiner Summary" and "Targets by SciMiner Full list", they may have been identified from the full text.


Targets by SciMiner Summary

HUGO ID Symbol Target Name #Occur ActualStr
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 239glt1 | EAAT2 | GLT1 |
10945SLC1A7solute carrier family 1 (glutamate transporter), member 711EAAT5 |
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 110EAAC1 | EAAT3 | EAAC1-knockout |
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 310GLAST | EAAT1 |
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))9SOD1 | SOD1-dependent | superoxide dismutase |
10944SLC1A6solute carrier family 1 (high affinity aspartate/glutamate transporter), member 67EAAT4 |
12805XDHxanthine dehydrogenase2xanthine oxidase |
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)1amyloid |
4571GRIA1glutamate receptor, ionotropic, AMPA 11glutamate receptor |

 

Targets by SciMiner Full list

HUGO ID Symbol Name ActualStr Score FlankingText
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3in the structures of at least three transporter subtypes (GLT1, GLT1 GLAST and EAAC1 and shown to regulate transport rate via
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 3GLAST2.5the structures of at least three transporter subtypes (GLT1, GLT1 GLAST and EAAC1 and shown to regulate transport rate via thiol-disulphide
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1EAAC13.0of at least three transporter subtypes (GLT1, GLT1 GLAST and EAAC1 and shown to regulate transport rate via thiol-disulphide redox interconversion
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 3GLAST2.5(or or excitatory amino acid carriers have now been identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 3EAAT12.5excitatory amino acid carriers have now been identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3amino acid carriers have now been identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2EAAT21.5carriers have now been identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 2
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1EAAC13.0have now been identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 2 3
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1EAAT32.5been identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 2 3 4 5
10944SLC1A6solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6EAAT41.0identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 2 3 4 5
10945SLC1A7solute carrier family 1 (glutamate transporter), member 7EAAT51.0identified GLAST (EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 2 3 4 5
10945SLC1A7solute carrier family 1 (glutamate transporter), member 7EAAT51.0(EAAT1), EAAT1 GLT1 (EAAT2), EAAT2 EAAC1 (EAAT3), EAAT3 EAAT4 and EAAT5 (Refs Refs 1 2 3 4 5
10944SLC1A6solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6EAAT41.0EAAT4 and EAAT5 have the highest Cl _amp_#x2212 conductances
10945SLC1A7solute carrier family 1 (glutamate transporter), member 7EAAT51.0EAAT4 and EAAT5 have the highest Cl _amp_#x2212 conductances
10945SLC1A7solute carrier family 1 (glutamate transporter), member 7EAAT51.0EAAT4 and EAAT5 have the highest Cl _amp_#x2212 conductances
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3In studies to localize the isoforms GLT1 and GLAST appear to be restricted to brain astrocytes 11
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 3GLAST2.5In studies to localize the isoforms GLT1 and GLAST appear to be restricted to brain astrocytes 11 12 and
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3GLT1 is the most abundant glutamate transporter and represents about 1%
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 3GLAST2.5The highest concentration of GLAST is found in the Bergmann glia of the cerebellar molecular
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3In astrocytic membranes GLT1 and GLAST localize preferentially to the parts of the plasma
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 3GLAST2.5In astrocytic membranes GLT1 and GLAST localize preferentially to the parts of the plasma membrane that
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3Moreover the expression of GLT1 and GLAST is under the control of neuronal soluble factors
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 3GLAST2.5Moreover the expression of GLT1 and GLAST is under the control of neuronal soluble factors including glutamate
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1EAAC13.0In the brain the EAAC1 protein and mRNA are found in neurones 15 16 where
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1EAAC13.0EAAC1 is not restricted to glutamatergic neurones and has now also
10944SLC1A6solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6EAAT41.0The fourth subtype EAAT4 is concentrated in the spines of Purkinje cells predominantly extrasynaptically
10945SLC1A7solute carrier family 1 (glutamate transporter), member 7EAAT51.0EAAT5 appears to be a retinal protein 5
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3tissue damage resulted from loss of the glial transporters particularly GLT1 (Ref Ref 25
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3Indeed knockout mice lacking GLT1 undergo lethal spontaneous seizures increased susceptibility to acute brain injury
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1EAAC1-knockout2.5In contrast EAAC1-knockout mice develop dicarboxylic aminoaciduria and no sign of neurodegeneration during
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3Indeed the transport activities of GLT1 EAAC1 and GLAST are equally inhibited by oxidants via a
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1EAAC13.0Indeed the transport activities of GLT1 EAAC1 and GLAST are equally inhibited by oxidants via a direct
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 3GLAST2.5Indeed the transport activities of GLT1 EAAC1 and GLAST are equally inhibited by oxidants via a direct action on
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1EAAC13.0EAAC1 GLT1 and GLAST exhibit redox-sensing properties
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3EAAC1 GLT1 and GLAST exhibit redox-sensing properties
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 3GLAST2.5EAAC1 GLT1 and GLAST exhibit redox-sensing properties
10944SLC1A6solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6EAAT41.0At present no information is available for EAAT4 and EAAT5
10945SLC1A7solute carrier family 1 (glutamate transporter), member 7EAAT51.0At present no information is available for EAAT4 and EAAT5
10945SLC1A7solute carrier family 1 (glutamate transporter), member 7EAAT51.0At present no information is available for EAAT4 and EAAT5
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1EAAC13.0EAAC1 GLAST GLT1 EAAT4 and EAAT5 carry different cysteine residues in
10941SLC1A3solute carrier family 1 (glial high affinity glutamate transporter), member 3GLAST2.5EAAC1 GLAST GLT1 EAAT4 and EAAT5 carry different cysteine residues in their
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3EAAC1 GLAST GLT1 EAAT4 and EAAT5 carry different cysteine residues in their sequences
10944SLC1A6solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6EAAT41.0EAAC1 GLAST GLT1 EAAT4 and EAAT5 carry different cysteine residues in their sequences ranging
10945SLC1A7solute carrier family 1 (glutamate transporter), member 7EAAT51.0EAAC1 GLAST GLT1 EAAT4 and EAAT5 carry different cysteine residues in their sequences ranging
10945SLC1A7solute carrier family 1 (glutamate transporter), member 7EAAT51.0EAAC1 GLAST GLT1 EAAT4 and EAAT5 carry different cysteine residues in their sequences ranging from a
10944SLC1A6solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6EAAT41.0in their sequences ranging from a minimum of two for EAAT4 to a maximum of 11 for EAAT5 (Ref Ref 5
10945SLC1A7solute carrier family 1 (glutamate transporter), member 7EAAT51.0of two for EAAT4 to a maximum of 11 for EAAT5 (Ref Ref 5
10945SLC1A7solute carrier family 1 (glutamate transporter), member 7EAAT51.0residues two are conserved among all the transporter subtypes except EAAT5 which has only one conserved cysteine
10939SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1EAAC13.0Glutamate transporters located in the postsynaptic compartment (e.g e.g EAAC1 or EAAT4 have an increased chance of exposure to noxious
10944SLC1A6solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6EAAT41.0transporters located in the postsynaptic compartment (e.g e.g EAAC1 or EAAT4 have an increased chance of exposure to noxious amounts of
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3glutamate uptake activity apparently owing to a selective loss of GLT1 in the spinal cord and motor cortex of patients with
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3The mechanism(s) mechanism s leading to loss of GLT1 are not fully understood
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3The steady-state level of GLT1 mRNA was apparently unchanged leading investigators initially to suspect a
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3or the internalization and/or and or degradation of post-translationally damaged GLT1 (Ref Ref 51
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3and/or and or producing a dominant negative effect on normal GLT1 (Ref Ref 52
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4gene encoding Cu 2 /Zn Zn 2 superoxide dismutase ( SOD1
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4Mice made transgenic for mutant SOD1 developed selective motoneurone pathology strongly resembling human ALS (Ref Ref
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD1-dependent1.4aetiology of sporadic forms may involve mechanisms similar to the SOD1-dependent defects of fALS (Ref Ref 55
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4Mutations in SOD1 not only reduce the capacity to detoxify superoxide but actually
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4Abnormalities of SOD1 may result in defective glutamate transport since transgenic mice expressing
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4in defective glutamate transport since transgenic mice expressing an ALS-linked SOD1 mutation show increased tyrosine nitration of glutamate transporters 43 and
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3tyrosine nitration of glutamate transporters 43 and marked loss of GLT1 in the spinal cord 58
620APPamyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)amyloid1.0A fragment of _amp_#x3b2 -amyloid (A_amp_#x3b2;), A_amp_#x3b2 the central constituent of neuritic plaques in Alzheimer's
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3shown to form adducts with a number of proteins including GLT1 by reaction at sulphydryls or other vulnerable groups 66
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2GLT12.3As the glutamate transporters GLT1 in particular are crucial in maintaining glutamate homeostasis 6 32
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4a result of altered function of mutant superoxide dismutase (SOD1) SOD1
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0specific _amp_#x2018;redox sensing' elements consisting of cysteine residues have been identified in the structures of at least three transporter subtypes glt1 glast and eaac1 and shown to regulate transport rate via thiol disulphide redox interconversion.
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0five different isoforms of glutamate transporters or excitatory amino acid carriers have now been identified: glast eaat1 glt1 eaat2 eaac1 eaat3 eaat4 and eaat5 refs [ 1 2 3 4 5 ] .
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0in studies to localize the isoforms glt1 and glast appear to be restricted to brain astrocytes [ 11 12 ] and are expressed in different proportions in different regions.
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0glt1 is the most abundant glutamate transporter and represents about 1% of the total brain membrane protein[ 6 13 ] with highest concentrations in the hippocampus and cerebral cortex.
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0in astrocytic membranes glt1 and glast localize preferentially to the parts of the plasma membrane that face neuropil with lower levels in the parts facing pia mater capillary endothelium other astrocytes and neuronal cell bodie
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0moreover the expression of glt1 and glast is under the control of neuronal soluble factors including glutamate itself [ 14 ].
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0the most dramatic elevation of extracellular glutamate levels and tissue damage resulted from loss of the glial transporters particularly glt1 ref [ 25 ] .
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0indeed knockout mice lacking glt1 undergo lethal spontaneous seizures increased susceptibility to acute brain injury and die prematurely with virtually no survivors three months after birth [ 26 ].
12805XDHxanthine dehydrogenasexanthine oxidase1.0toxic pathways include ca 2+ dependent activation of nitric oxide no synthase phospholipase a 2 and xanthine oxidase which can all contribute to an aberrant formation of reactive oxygen species.
12805XDHxanthine dehydrogenasexanthine oxidase1.0reactive oxygen species generated by hydrogen peroxide h 2 o 2 or by xanthine oxidase activation inhibit [ 3 h]glutamate uptake in cultured astrocytes and reduce the transport associated current under voltage clamp with minor or no effect on the resting membrane conductance [ 34 ].
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0indeed the transport activities of glt1 eaac1 and glast are equally inhibited by oxidants via a direct action on the transporter proteins.
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0eaac1 glt1 and glast exhibit redox sensing properties.
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0eaac1 glast glt1 eaat4 and eaat5 carry different cysteine residues in their sequences ranging from a minimum of two for eaat4 to a maximum of 11 for eaat5 ref [ 5 ] .
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0sporter defect and neurodegeneration has been demonstrated by rothstein and collegues [ 50 ]: they have reported a remarkable loss of glutamate uptake activity apparently owing to a selective loss of glt1 in the spinal cord and motor cortex of patients with the disease.
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0the mechanism s leading to loss of glt1 are not fully understood.
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0the steady state level of glt1 mrna was apparently unchanged leading investigators initially to suspect a block of translation or the internalization and/or degradation of post translationally damaged glt1 ref [ 51 ] .
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0 mrna was apparently unchanged leading investigators initially to suspect a block of translation or the internalization and/or degradation of post translationally damaged glt1 ref [ 51 ] .
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0 of abnormal glt1mrnas including intron retention and exon skipping whose processing could lead to unstable proteins undergoing rapid degradation and/or producing a dominant negative effect on normal glt1 ref [ 52 ] .
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0ies by rosen and colleagues [ 53 ] linked als to reactive oxygen species toxicity since they showed that 15_amp_#x2013;20% of fals patients carry mis sense mutations in the gene encoding cu 2+ /zn 2+ superoxide dismutase sod1 .
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0s of sod1 may result in defective glutamate transport since transgenic mice expressing an als linked sod1 mutation show increased tyrosine nitration of glutamate transporters[ 43 ] and marked loss of glt1 in the spinal cord [ 58 ].
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0ion of 4 hydroxynonenal an aldehydic product of lipid peroxidative processes which by itself mimicked uptake inhibition. 4 hydroxynomenal was shown to form adducts with a number of proteins including glt1 by reaction at sulphydryls or other vulnerable groups [ 66 ].
10940SLC1A2solute carrier family 1 (glial high affinity glutamate transporter), member 2glt11.0as the glutamate transporters glt1 in particular are crucial in maintaining glutamate homeostasis[ 6 32 33 ] eventual oxidative damage of the transporters in vivo is predicted to have major neurotoxic consequences.
4571GRIA1glutamate receptor, ionotropic, AMPA 1glutamate receptor1.0ber of different mechanisms may contribute to [ca 2+ ] i rise including direct influx via n methyl aspartate nmda or rs amino 3 hydroxy 5 methyl 4 isoxazole propionic acid ampa receptors metabotropic glutamate receptor mediated release from the internal stores activation of voltage dependent ca 2+ channels and reversal of na + /ca 2+ exchange.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0in amyotrophic lateral sclerosis peroxynitrite onoo _amp_#x2212; or other noxious ros can be formed as a result of altered function of mutant superoxide dismutase sod1 .