Genomes and Genes
glutamate plasma membrane transport proteins
Summary: A family of plasma membrane neurotransmitter transporter proteins that couple the uptake of GLUTAMATE with the import of SODIUM ions and PROTONS and the export of POTASSIUM ions. In the CENTRAL NERVOUS SYSTEM they regulate neurotransmission through synaptic reuptake of the excitatory neurotransmitter glutamate. Outside the central nervous system they function as signal mediators and regulators of glutamate metabolism.
- Zerangue N, Kavanaugh M. Interaction of L-cysteine with a human excitatory amino acid transporter. J Physiol. 1996;493 ( Pt 2):419-23 pubmed..5. Because the EAAT3 transporter is also expressed in tissues including kidney and intestine, the results suggest the possibility of a heretofore unrecognized mechanism of L-cysteine uptake in peripheral tissues as well as in brain. ..
- Aronica E, Gorter J, Ijlst Keizers H, Rozemuller A, Yankaya B, Leenstra S, et al. Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur J Neurosci. 2003;17:2106-18 pubmed
- Grewer C, Rauen T. Electrogenic glutamate transporters in the CNS: molecular mechanism, pre-steady-state kinetics, and their impact on synaptic signaling. J Membr Biol. 2005;203:1-20 pubmed..Finally, we discuss how synaptic glutamate transporters impact on glutamate receptor activity and how transporters may shape excitatory synaptic transmission. ..
- Matthias K, Kirchhoff F, Seifert G, Hüttmann K, Matyash M, Kettenmann H, et al. Segregated expression of AMPA-type glutamate receptors and glutamate transporters defines distinct astrocyte populations in the mouse hippocampus. J Neurosci. 2003;23:1750-8 pubmed..The observed heterogeneity of cells with GFAP promoter-regulated EGFP expression and S100beta/GFAP immunoreactivity challenges the hitherto accepted definition of astrocytes. ..
- Jensen A, Brauner Osborne H. Pharmacological characterization of human excitatory amino acid transporters EAAT1, EAAT2 and EAAT3 in a fluorescence-based membrane potential assay. Biochem Pharmacol. 2004;67:2115-27 pubmed
- Lin C, Orlov I, Ruggiero A, Dykes Hoberg M, Lee A, Jackson M, et al. Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18. Nature. 2001;410:84-8 pubmed..These studies show that glutamate transport proteins can be regulated potently and that GTRAP can modulate the transport functions ascribed to EAAC1. GTRAP3-18 may be important in regulating the metabolic function of EAAC1...
- Hurtado O, Moro M, Cárdenas A, Sanchez V, Fernández Tomé P, Leza J, et al. Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport. Neurobiol Dis. 2005;18:336-45 pubmed..The present study was designed to search for mechanisms of citicoline neuroprotective properties using in vivo and in vitro models of brain ischemia...
- Shigeri Y, Shimamoto K, Yasuda Kamatani Y, Seal R, Yumoto N, Nakajima T, et al. Effects of threo-beta-hydroxyaspartate derivatives on excitatory amino acid transporters (EAAT4 and EAAT5). J Neurochem. 2001;79:297-302 pubmed..These results indicate that EAATs 4 and 5 show different sensitivities to THA analogs although they share properties of a glutamate-gated chloride channel. ..
- Fairman W, Vandenberg R, Arriza J, Kavanaugh M, Amara S. An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature. 1995;375:599-603 pubmed..Thus EAAT4 combines the re-uptake of neurotransmitter with a mechanism for increasing chloride permeability, both of which could regulate excitatory neurotransmission. ..
- Tan E, Foo J, Tan L, Au W, Prakash K, Ng E, et al. SLC1A2 variant associated with essential tremor but not Parkinson disease in Chinese subjects. Neurology. 2013;80:1618-9 pubmed publisher..In addition, we also investigated the variant in patients with Parkinson disease (PD) because the GWAS LINGO1 variant has been implicated in both ET and PD and etiologic links between the conditions have been suggested.(6.)..
- Smith R, Haroutunian V, Davis K, Meador Woodruff J. Expression of excitatory amino acid transporter transcripts in the thalamus of subjects with schizophrenia. Am J Psychiatry. 2001;158:1393-9 pubmed
- Choudary P, Molnar M, Evans S, Tomita H, Li J, Vawter M, et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A. 2005;102:15653-8 pubmed..These findings point to previously undiscovered molecular underpinnings of the pathophysiology of major depression and offer potentially new pharmacological targets for treating depression. ..
- Grewer C, Madani Mobarekeh S, Watzke N, Rauen T, Schaper K. Substrate translocation kinetics of excitatory amino acid carrier 1 probed with laser-pulse photolysis of a new photolabile precursor of D-aspartic acid. Biochemistry. 2001;40:232-40 pubmed
- Thier S, Lorenz D, Nothnagel M, Poremba C, Papengut F, Appenzeller S, et al. Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor. Neurology. 2012;79:243-8 pubmed publisher..Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET. ..
- Conti F, Debiasi S, Minelli A, Rothstein J, Melone M. EAAC1, a high-affinity glutamate tranporter, is localized to astrocytes and gabaergic neurons besides pyramidal cells in the rat cerebral cortex. Cereb Cortex. 1998;8:108-16 pubmed
- Melzer N, Biela A, Fahlke C. Glutamate modifies ion conduction and voltage-dependent gating of excitatory amino acid transporter-associated anion channels. J Biol Chem. 2003;278:50112-9 pubmed..These results are incompatible with the notion that glutamate only increases the open probability of the anion pore associated with glutamate transporters and demonstrate unique gating mechanisms of EAAT-associated anion channels. ..
- Huang Z, Tajkhorshid E. Dynamics of the extracellular gate and ion-substrate coupling in the glutamate transporter. Biophys J. 2008;95:2292-300 pubmed publisher..Finally, binding of Na2 locks the extracellular gate and completes the formation of the occluded state of GluT. ..
- Tao F, Liaw W, Zhang B, Yaster M, Rothstein J, Johns R, et al. Evidence of neuronal excitatory amino acid carrier 1 expression in rat dorsal root ganglion neurons and their central terminals. Neuroscience. 2004;123:1045-51 pubmed..Our findings suggest that EAAC1 might play an important role in transmission and modulation of nociceptive information via the regulation of pre-synaptically released glutamate. ..
- Romera C, Hurtado O, Botella S, Lizasoain I, Cárdenas A, Fernández Tomé P, et al. In vitro ischemic tolerance involves upregulation of glutamate transport partly mediated by the TACE/ADAM17-tumor necrosis factor-alpha pathway. J Neurosci. 2004;24:1350-7 pubmed..These data demonstrate that neuroprotection induced by IPC involves upregulation of glutamate uptake partly mediated by TACE overexpression. ..
- Berger U, Hediger M. Comparative analysis of glutamate transporter expression in rat brain using differential double in situ hybridization. Anat Embryol (Berl). 1998;198:13-30 pubmed..These results provide more detailed information about the precise cellular localization of these three glutamate transporters and their regulation at the mRNA level...
- Bale A, Tu Y, Carpenter Hyland E, Chandler L, Woodward J. Alterations in glutamatergic and gabaergic ion channel activity in hippocampal neurons following exposure to the abused inhalant toluene. Neuroscience. 2005;130:197-206 pubmed..The results from this study suggest that toluene induces compensatory responses in the functional expression of ion channels that regulate neuronal excitability. ..
- Willmore L, Ueda Y. Posttraumatic epilepsy: hemorrhage, free radicals and the molecular regulation of glutamate. Neurochem Res. 2009;34:688-97 pubmed publisher..Administration of antioxidants to animals causes interruption of the sequence of brain injury responses induced by hemorrhage, suggesting that such a strategy needs to be evaluated in patients with traumatic brain injury. ..
- Rebillard G, Ruel J, Nouvian R, Saleh H, Pujol R, Dehnes Y, et al. Glutamate transporters in the guinea-pig cochlea: partial mRNA sequences, cellular expression and functional implications. Eur J Neurosci. 2003;17:83-92 pubmed
- Scott H, Gebhardt F, Mitrovic A, Vandenberg R, Dodd P. Glutamate transporter variants reduce glutamate uptake in Alzheimer's disease. Neurobiol Aging. 2011;32:553.e1-11 pubmed publisher..These results have implications for the treatment of AD as modulators of EAAT2 splicing and/or glutamate uptake would augment current therapies aimed at blocking glutamate receptors. ..
- Eskandari S, Kreman M, Kavanaugh M, Wright E, Zampighi G. Pentameric assembly of a neuronal glutamate transporter. Proc Natl Acad Sci U S A. 2000;97:8641-6 pubmed..The pentameric structure of EAAT3 offers new insights into its function as both a glutamate transporter and a glutamate-gated chloride channel. ..
- Soria F, Perez Samartin A, Martin A, Gona K, Llop J, Szczupak B, et al. Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage. J Clin Invest. 2014;124:3645-55 pubmed publisher..Altogether, these data suggest that cystine/glutamate antiporter function is increased in ischemia, contributing to elevated extracellular glutamate concentration, overactivation of extrasynaptic NMDARs, and ischemic neuronal death. ..
- Mäenpää H, Gegelashvili G, Tähti H. Expression of glutamate transporter subtypes in cultured retinal pigment epithelial and retinoblastoma cells. Curr Eye Res. 2004;28:159-65 pubmed..Unaltered steady-state expression of this carrier and chloride-channel protein hints at posttranslational mechanisms of regulation of EAAT4. ..
- Sagot E, Jensen A, Pickering D, Pu X, Umberti M, Stensbøl T, et al. Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human excitatory amino acid transporter subtype 2. J Med Chem. 2008;51:4085-92 pubmed publisher..The compound also displayed very low affinities toward ionotropic and metabotropic Glu receptors, making it the most selective EAAT2 inhibitor described so far. ..
- Talukder J, Kekuda R, Saha P, Arthur S, Sundaram U. Identification and characterization of rabbit small intestinal villus cell brush border membrane Na-glutamine cotransporter. Am J Physiol Gastrointest Liver Physiol. 2008;295:G7-G15 pubmed publisher..Thus this study describes the identification, cloning, and characterization of the Na-amino acid cotransporter responsible for the assimilation of a critical amino acid by the absorptive villus cells in the mammalian small intestine. ..
- Levenson J, Weeber E, Selcher J, Kategaya L, Sweatt J, Eskin A. Long-term potentiation and contextual fear conditioning increase neuronal glutamate uptake. Nat Neurosci. 2002;5:155-61 pubmed..These results indicate that regulation of glutamate uptake may be important for maintaining the level of synaptic strength during long-term changes in synaptic efficacy. ..
- Velaz Faircloth M, McGraw T, alandro M, Fremeau R, Kilberg M, Anderson K. Characterization and distribution of the neuronal glutamate transporter EAAC1 in rat brain. Am J Physiol. 1996;270:C67-75 pubmed..Sections that were emulsion-dipped and counterstained with cresyl violet revealed EAAC1 labeling localized exclusively over neuronal cell bodies, including some nonglutamatergic neurons such as spinal cord ventral horn cells...
- García Tardón N, González González I, Martínez Villarreal J, Fernández Sánchez E, Giménez C, Zafra F. Protein kinase C (PKC)-promoted endocytosis of glutamate transporter GLT-1 requires ubiquitin ligase Nedd4-2-dependent ubiquitination but not phosphorylation. J Biol Chem. 2012;287:19177-87 pubmed publisher..These results indicate that GLT-1 endocytosis is independent of its phosphorylation and that Nedd4-2 mediates PKC-dependent down-regulation of the transporter. ..
- Jacobs V, De Leo J. Increased glutamate uptake in astrocytes via propentofylline results in increased tumor cell apoptosis using the CNS-1 glioma model. J Neurooncol. 2013;114:33-42 pubmed publisher..These data suggest that astrocytes in the tumor microenvironment can be targeted by the drug, propentofylline, affecting tumor cell growth. ..
- Kugler P, Schleyer V. Developmental expression of glutamate transporters and glutamate dehydrogenase in astrocytes of the postnatal rat hippocampus. Hippocampus. 2004;14:975-85 pubmed..These observations suggest that the extent of glutamate transporter expression and of glutamate-metabolizing GDH activity in astrocytes is intimately correlated with the formation of glutamatergic synapses in the developing hippocampus. ..
- Fournier K, Gonzalez M, Robinson M. Rapid trafficking of the neuronal glutamate transporter, EAAC1: evidence for distinct trafficking pathways differentially regulated by protein kinase C and platelet-derived growth factor. J Biol Chem. 2004;279:34505-13 pubmed..The data also suggest that basal and regulated pools of EAAC1 exist in distinct compartments. ..
- Ward M, Jobling A, Puthussery T, Foster L, Fletcher E. Localization and expression of the glutamate transporter, excitatory amino acid transporter 4, within astrocytes of the rat retina. Cell Tissue Res. 2004;315:305-10 pubmed..These results suggest that astrocytes within the retina are well placed to provide mechanisms for glutamate removal as well as controlling cellular excitability. ..
- Chen Y, Swanson R. The glutamate transporters EAAT2 and EAAT3 mediate cysteine uptake in cortical neuron cultures. J Neurochem. 2003;84:1332-9 pubmed..The findings suggest that neuronal EAAT activity can be a rate-limiting step for neuronal glutathione synthesis and that the primary function of EAATs expressed by neurons in vivo may be to transport cysteine. ..
- Poulsen M, Vandenberg R. Niflumic acid modulates uncoupled substrate-gated conductances in the human glutamate transporter EAAT4. J Physiol. 2001;534:159-67 pubmed
- Gaillet S, Plachez C, Malaval F, Bézine M, Recasens M. Transient increase in the high affinity [3H]-L-glutamate uptake activity during in vitro development of hippocampal neurons in culture. Neurochem Int. 2001;38:293-301 pubmed..This latter activity could potentially be related to the transient expression of the glial GLAST transporter in neurons...
- Brauner Osborne H, Hermit M, Nielsen B, Krogsgaard Larsen P, Johansen T. A new structural class of subtype-selective inhibitor of cloned excitatory amino acid transporter, EAAT2. Eur J Pharmacol. 2000;406:41-4 pubmed..S)-TDPA thus represents a new structural class of EAAT2 inhibitor that will serve as a lead for the design of EAAT selective inhibitors...
- Rauen T, Wiessner M. Fine tuning of glutamate uptake and degradation in glial cells: common transcriptional regulation of GLAST1 and GS. Neurochem Int. 2000;37:179-89 pubmed
- Yu S, Chen C, Chen Y, Chang C, Chang H, Lyu R, et al. SLC1A2 variant is associated with essential tremor in Taiwanese population. PLoS ONE. 2013;8:e71919 pubmed publisher..A replication study in another independent population is of importance to validate this association. ..
- De Felice B, Guida M, Guida M, Coppola C, De Mieri G, Cotrufo R. A miRNA signature in leukocytes from sporadic amyotrophic lateral sclerosis. Gene. 2012;508:35-40 pubmed publisher..We suggest that miRNAs profiles found in the peripheral blood leukocytes from sALS patients can be relevant to understand the pathogenesis of sALS and/or used as biomarkers of the disease. ..
- Larsson H, Tzingounis A, Koch H, Kavanaugh M. Fluorometric measurements of conformational changes in glutamate transporters. Proc Natl Acad Sci U S A. 2004;101:3951-6 pubmed..The data further suggest that an increase in proton concentrations slows the reverse transport of glutamate, which may play a neuro-protective role during ischemia. ..
- Cucchiaroni M, Viscomi M, Bernardi G, Molinari M, Guatteo E, Mercuri N. Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative beta-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons. J Neurosci. 2010;30:5176-88 pubmed publisher..Moreover, environmental exposure to BMAA might possibly also contribute to idiopathic PD. ..
- Hatakeyama D, Mita K, Kobayashi S, Sadamoto H, Fujito Y, Hiripi L, et al. Glutamate transporters in the central nervous system of a pond snail. J Neurosci Res. 2010;88:1374-86 pubmed publisher..Our results confirmed the presence of GLU uptake systems in the Lymnaea CNS and showed that LymEAAT is required for proper rhythm generation, particularly for generation of the feeding rhythm. ..
- Chen W, Sung C, Jean Y, Su T, Wang H, Ho J, et al. Suppressive effects of intrathecal granulocyte colony-stimulating factor on excessive release of excitatory amino acids in the spinal cerebrospinal fluid of rats with cord ischemia: role of glutamate transporters. Neuroscience. 2010;165:1217-32 pubmed publisher..We propose that i.t. G-CSF possesses an ability to reduce the extent of spinal cord ischemia-induced excitotoxicity by inducing the expression of glutamate transporters. ..
- Matsumoto Y, Suzuki A, Ishii G, Oshino S, Otani K, Goto K. The -181 A/C polymorphism in the excitatory amino acid transporter-2 gene promoter affects the personality trait of reward dependence in healthy subjects. Neurosci Lett. 2007;427:99-102 pubmed..021) but not in males. The present study thus suggests that the -181 A/C polymorphism in the EAAT2 gene promoter affects the personality trait of reward dependence in healthy subjects. ..
- Cimarosti H, Jones N, O Shea R, Pow D, Salbego C, Beart P. Hypoxic preconditioning in neonatal rat brain involves regulation of excitatory amino acid transporter 2 and estrogen receptor alpha. Neurosci Lett. 2005;385:52-7 pubmed..The endogenous molecular mechanisms modulated by hypoxia preconditioning may contribute to the development of hypoxia-induced ischemic tolerance, and may provide novel therapeutic targets for the treatment of cerebral ischemia. ..
- Ueda Y, Doi T, Tsuru N, Tokumaru J, Mitsuyama Y. Expression of glutamate transporters and ionotropic glutamate receptors in GLAST knockout mice. Brain Res Mol Brain Res. 2002;104:120-6 pubmed
- Shafqat S, Tamarappoo B, Kilberg M, Puranam R, McNamara J, Guadaño Ferraz A, et al. Cloning and expression of a novel Na(+)-dependent neutral amino acid transporter structurally related to mammalian Na+/glutamate cotransporters. J Biol Chem. 1993;268:15351-5 pubmed..SATT may represent one of multiple activities that exhibit System ASC-like transport characteristics in diverse tissues and cell lines. ..