Review Article The family of sodium-dependent glutamate transporters: a focus on the GLT-1/EAAT2 subtype

The acidic amino acids, glutamate and aspartate, are the predominant excitatory neurotransmitters in the mammalian CNS. Under many pathologic conditions, these excitatory amino acids (EAAs) accumulate in the extracellular fluid in CNS and the resultant excessive activation of EAA receptors contributes to brain injury through a process known as excitotoxicity. Unlike many other neurotransmitters, there is no evidence for extracellular metabolism of EAAs, rather, they are cleared by Na⁺-dependent transport mechanisms. Therefore, this transport process is important for ensuring crisp synaptic signaling as well as limiting the excitotoxic potential of EAAs. With the cloning of five distinct EAA transporters, a variety of tools were developed to characterize individual transporter subtypes, including specific antibodies, expression systems, and probes to delete/knock-down expression of each subtype. These tools are beginning to provide fundamental information that has the potential to impact our understanding of EAA physiology and pathophysiology. For example, biophysical studies of the cloned transporters have led to the observation that some subtypes function as ligand-gated ion channels as well as transporters. With these reagents, it has also been possible to explore the relative contributions of each transporter to the clearance of extracellular EAAs and to begin to examine the regulation of specific transporter subtypes. In this review, an overview of the properties of the transporter subtypes will be presented. The evidence which suggests that the transporter, GLT1/EAAT2, may be sufficient to explain a large percentage of forebrain transport will be critically reviewed. Finally, the studies of regulation of GLT-1 in vitro and in vivo will be described.     

The in vitro uptake of glutamate in GLAST and GLT-1 transfected mutant CHO-K1 cells is inhibited by manganese

In the central nervous system (CNS), extracellular concentrations of amino acids (e.g., aspartate, glutamate) and divalent metals (e.g., zinc, copper, manganese) are primarily regulated by astrocytes. Adequate glutamate homeostasis and control over extracellular concentrations of these excitotoxic amino acids are essential for the normal functioning of the brain. Not only is glutamate of central importance for nitrogen metabolism but, along with aspartate, it is the primary mediator of excitatory pathways in the brain. Similarly, the maintenance of proper Mn levels is important for normal brain function. Brain glutamate is removed from the extracellular fluid mainly by astrocytes via high affinity astroglial Na+-dependent excitatory amino acid transporters, glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1). The effects of Mn on specific glutamate transporters have yet to be determined. As a first step in this process, we examined the effects of Mn on the transport of [D-2, 3-3H]D-aspartate, a non-metabolizable glutamate analog, in Chinese hamster ovary cells (CHO) transfected with two glutamate transporter subtypes, GLAST (EAAT1) or GLT-1 (EAAT2). Mn-mediated inhibition of glutamate transport in the CHO-K1 cell line DdB7 was pronounced in both the GLT-1 and GLAST transfected cells. This resulted in a statistically significant inhibition (p<0.05) of glutamate uptake compared with transfected control in the absence of Mn treatment. These studies suggest that Mn accumulation in the CNS might contribute to dysregulation of glutamate homeostasis.     

Glutamate: A major neuroendocrine excitatory signal mediating steroid effects on gonadotropin secretion

The preovulatory gonadotropin surge is induced by progesterone in the cycling female rat or in the ovariectomized estrogen-treated female rat after adequate estrogen-priming activity is present. The source of progesterone under physiological conditions could be the ovary and/or the adrenal. Since the GnRH neuron does not possess estrogen and progesterone receptors, its function is modulated by other CNS neurotransmitters and neurosecretory products. Among these, excitatory amino acids (EAAs) have now been shown to play an important role in the regulation of pulsatile gonadotropin release, induction of puberty and preovulatory and steroid-induced gonadotropin surges. Glutamate, the major endogenous EAA exerts its action through ionotropic and metabotropic receptors. The ionotropic receptors consist of two major classes, the NMDA (N-methyl-D-aspartate) and non-NMDA: kainate and AMPA ( --amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. EAA receptors are found in hypothalamic areas involved with reproduction. While both NMDA and non-NMDA receptors are involved in the regulation of LH secretion, the NMDA receptors appear to be involved with the regulation of puberty and FSH secretion as well. Steroids increase the release rates of glutamate and aspartate in the preoptic area during the gonadotropin surge. Steroids may also regulate the hypothalamic AMPA receptors.     

Transporter mediated GABA release in the retina: Role of excitatory amino acids and dopamine

In general, the release of neurotransmitters in the central nervous system is accomplished by a calcium-dependent process which constitutes a common feature of exocytosis, a conserved mechanism for transmitter release in all species. However, neurotransmitters can also be released by the reversal of their transporters. In the retina, a large portion of GABA is released by this mechanism, which is under the control of neuroactive agents, such as excitatory amino acids and dopamine. In this review, we will focus on the transporter mediated GABA release and the role played by excitatory amino acids and dopamine in this process. First, we will discuss the works that used radiolabeled GABA to study the outflow of the neurotransmitter and then the works that took into consideration the endogenous pool of GABA and the topography of GABAergic circuits influenced by excitatory amino acids and dopamine.     

Transporter mediated GABA release in the retina: role of excitatory amino acids and dopamine

In general, the release of neurotransmitters in the central nervous system is accomplished by a calcium-dependent process which constitutes a common feature of exocytosis, a conserved mechanism for transmitter release in all species. However, neurotransmitters can also be released by the reversal of their transporters. In the retina, a large portion of GABA is released by this mechanism, which is under the control of neuroactive agents, such as excitatory amino acids and dopamine. In this review, we will focus on the transporter mediated GABA release and the role played by excitatory amino acids and dopamine in this process. First, we will discuss the works that used radiolabeled GABA to study the outflow of the neurotransmitter and then the works that took into consideration the endogenous pool of GABA and the topography of GABAergic circuits influenced by excitatory amino acids and dopamine.     

Amino acid neurotransmitter transporters: Structure,function, and molecular diversity

Many biologically active compounds including neurotransmitters, metabolic precursors, and certain drugs are accumulated intracellularly by transporters that are coupled to the transmembrane Na⁺ gradient. Amino acid neurotransmitter transporters play a key role in the regulation of extracellular amino acid concentrations and termination of neurotransmission in the CNS

1 Abbreviations: CNS, central nervous system; GABA, γ-aminobutyric acid; cDNA, complementary deoxyribonucleic acid; mRNA, messenger ribonucleic acid; NMDA, N-methyl-D-aspartate; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate; DAG, diacyl glycerol; R59022, DAG kinase inhibitor; AA, arachidonic acid; ACHC, cis-3-aminocyclohexanecarboxylic acid; GAT-A, ACHC-sensitive GABA transporter; GAT-B, β-alanine-sensitive GABA transporter; GLY-1 and GLYT-1, glycine transporters; PROT-1, proline transporter; BGT-1, betaine transporter.

. Transporters for the major amino acid neurotransmitters glutamate, GABA, and glycine are found in both neurons and glial cells. Recent work has resulted in the identification of cDNAs encoding several amino acid neurotransmitter transport proteins, all of which belong to the Na⁺-and Cl^?-dependent transporter gene family. The diversity of this family suggests a degree of transporter heterogeneity that is greater than that indicated by biochemical and pharmacological studies.     

How did the neurotransmitter cross the bilayer? A closer view

Plasma membrane neurotransmitter transporters for monoamines, GABA, glycine and excitatory amino acids are homologous to two sizable families of bacterial amino acid transporters. Recently, a high resolution structure was determined for a thermophilic glutamate transporter. Also, a bacterial tryptophan transporter related to the family of biogenic amine neurotransmitter transporters was functionally expressed. Structural insights from these and other bacterial transporters will help to rationalize the mechanisms for the increasingly complex functions that have been described for mammalian transporters, in addition to their modes of regulation. We touch on recent insights into the functions of neurotransmitter transporters in their physiological contexts.     

Serum selenium levels in the US population: Third National Health and Nutrition Examination Survey, 1988-1994

The published literature on serum selenium levels in the US population describes studies on small samples that may not be representative of the US population. This analysis provides the first nationally representative serum selenium levels in the US population by age group, sex, race-ethnicity, poverty income ratio (PIR), geographic region, and urban status. The Third National Health and Nutrition Examination Survey (NHANES III) is a national population-based cross-sectional survey with an in-person interview and serum selenium measurements. For the 18,597 persons for whom serum selenium values were available in NHANES III, the mean concentration was 1.58 μmol/L and the median concentration was 1.56 μmol/L. Mean serum selenium levels differed by age group, sex, race-ethnicity, PIR, and geographic region. The US population has slight differences in serum selenium levels by demographic factors.     

Excitatory amino acid receptor-mediated neuronal signal transduction: modulation by polyamines and calcium

Molecular and Cellular Biochemistry - The excitatory amino acids (EAA), L-glutamate and L-aspartate were initially advanced as excitatory neurotransmitters some 30 years ago but in the past few...     

Reversible Activation of Glutamate Transport in Rat Brain Glia by Protein Kinase C and an Okadaic Acid-Sensitive Phosphoprotein Phosphatase

High-affinity L-glutamate (GLU) transport is an important regulator of excitatory amino acid (EAA) concentrations in brain extracellular fluid and may play a key role in excitatory synaptic transmission. In view of evidence that EAA transporters (EAAT) are heterogenous and contain consensus sites for phosphorylation, this investigation was undertaken to contrast the effects of transporter phosphorylation in fractions derived from glia and neurons (synaptosomes) of the adult rat forebrain. Treatment with phorbol-12,13-dibutyrate (PDBu), an activator of protein kinase C (PKC), increased the maximal rate of GLU transport in glial plasmalemmal vesicles by greater than 50 percent (237 ± 18 vs. 365 ± 27 pmol/mg protein/90s, p < 0.05) but caused no change in synaptosomes. The effect by PDBu was concentration and time-dependent and was inhibited completely by the PKC inhibitor calphostin C. Inhibition of serine-threonine phosphoprotein phosphatases with okadaic acid produced similar effects which were not additive with PDBu. Together, these results demonstrate that glial EAAT can be regulated by multiple phosphorylation processes.     

Regulation of Growth Hormone (GH) secretion by different glutamate receptor subtypes in the rat

Summary. It has been firmly established that excitatory amino acids (EAAs), such as glutamate, are pivotal elements in the hypothalamic circuitry involved in the control of pituitary function. The actions of EAAs are mediated by different postsynaptic receptor subtypes, which include N-methyl D-aspartate (NMDA), kainate (KA), 2-amino-3-hydroxy-5 methyl-4-isoxazol propionic acid (AMPA) and metabotropic receptors. In this review, we summarize our experimental work on the role of EAA neurotransmission in the control of GH secretion in the rat. Detailed characterization of the effects of agonists and antagonists of glutamate receptors on GH release revealed that activation of NMDA, KA and AMPA receptors at different age-points resulted in clear-cut stimulation of GH secretion, although age- and sex-dependent differences were detected in the pattern of response to the different agonists. This stimulatory action was proven nitric oxide (NO)-dependent and not exerted at the pituitary level. In addition, evaluation of the role of hypothalamic GH-releasing hormone (GHRH) in the stimulatory action of NMDA by means of immunoneutralization of endogenous GHRH or destruction of GHRH producing neurons suggested the involvement of signals other than GHRH in this response. Further, evidence was obtained on the modulation of the EAA system by gonadal factors, and on the physiological relevance of EAA pathways in the regulation of pulsatile GH release. In conclusion, our data using the rat as animal model provide evidence for a pivotal role of glutamate pathways in the regulation of GH secretion throughout the life-span. Received May 5, 1999, Accepted July 28, 1999     

Electrogenic Glutamate Transporters in the CNS: Molecular Mechanism,Pre-steady-state Kinetics,and their Impact on Synaptic Signaling

Glutamate is the major excitatory neurotransmitter in the mammalian CNS. The spatiotemporal profile of the glutamate concentration in the synapse is critical for excitatory synaptic signalling. The control of this spatiotemporal concentration profile requires the presence of large numbers of synaptically localized glutamate transporters that remove pre-synaptically released glutamate by uptake into neurons and adjacent glia cells. These glutamate transporters are electrogenic and utilize energy stored in the transmembrane potential and the Na⁺/K⁺-ion concentration gradients to accumulate glutamate in the cell. This review focuses on the kinetic and electrogenic properties of glutamate transporters, as well as on the molecular mechanism of transport. Recent results are discussed that demonstrate the multistep nature of the transporter reaction cycle. Results from pre-steady-state kinetic experiments suggest that at least four of the individual transporter reaction steps are electrogenic, including reactions associated with the glutamate-dependent transporter halfcycle. Furthermore, the kinetic similarities and differences between some of the glutamate transporter subtypes and splice variants are discussed. A molecular mechanism of glutamate transport is presented that accounts for most of the available kinetic data. Finally, we discuss how synaptic glutamate transporters impact on glutamate receptor activity and how transporters may shape excitatory synaptic transmission.     

Redefining chemical anatomy of glutamatergic neurotransmission

With the recent identification of the two isoforms of vesicular glutamate transporters VGLUT1 and VGLUT2 and of the presumed neuronal glutamine transporter SAT1 novel tools have been made available to unequivocally define the anatomy of glutamatergic pathways on the cellular and synaptic level. Using highly specific antisera and cRNA probes two distinct glutamatergic pathways expressing either VGLUT1 or VGLUT2 could be detected throughout the central nervous system. Areas where VGLUT1 predominated included the cerebral and cerebellar cortex and the hippocampus. VGLUT2 was mainly expressed in the thalamus, hypothalamus and brain stem. VGLUT1 and VGLUT2 synapses exhibited distinct region- and pathway-specific relationships with each other and with other classical transmitter and peptidergic systems. The glutamine transporter SAT1 was expressed in CNS neurons and in ependymal cells. Neuronal SAT1 expression comprised virtually all glutamatergic neurons but also specific subsets of cholinergic, GABAergic and aminergic neurons in the CNS. In addition to widespread expression of VGLUT1 and VGLUT2 in the CNS, peripheral tissues such as sensory neurons and pancreatic islet cells differentially expressed VGLUT isoforms and SAT1.
Our results suggest pathway-specific functional duality in the regulation of vesicular glutamate release at excitatory synapses and provide evidence for glutamine transport and metabolism in excitatory glutamatergic and diverse nonglutamatergic neurons as well.     

Characterization of an Atypical Member of the Na+/Cl−-Dependent Transporter Family: Chromosomal Localization and Distribution in GABAergic and Glutamatergic Neurons in the Rat Brain

Abstract: A 3.7-kb cDNA fragment, designated rat-XT1, was isolated from a rat whole-brain cDNA library. The nucleotide sequence of XT1 codes for a 727 amino acid protein with a calculated molecular mass of 81,139 Da and 12 putative transmembrane domains. This protein shares significant homology (28–32%) with the monoamine- (dopamine, norepinephrine, serotonin), amino acid- (taurine, proline, GABA, glycine), choline-, and betaine-, Na⁺/Cl^?-dependent transporters. The homology is especially high within the first, second, sixth, and eighth transmembrane domains (45–75%). Thus, XT1 clearly belongs to the Na⁺/Cl^?-dependent neurotransmitter transporter superfamily. However, XT1 may define a new subfamily of transporter because it differs structurally from other members of this family in that the extracellular loop linking transmembrane domains 7 and 8 and the C-terminal tail are significantly larger in size. Transient or stable expression of rat-XT1 failed to confer to the transfected cells the ability to transport actively any of the >60 established or putative neurotransmitter substances assessed. Northern blot analyses of peripheral and neural tissues demonstrated that expression of the 8-kb XT1 mRNA is essentially restricted to the nervous system. In situ hybridization demonstrated a broad but discrete localization of XT1 message in the CNS, particularly in the cerebellum (Purkinje and granular cell layers), the hippocampus (pyramidal and granular cell layers), and the thalamus and throughout the cerebral cortex. This distribution parallels that of the neurotransmitters glutamate and aspartate; however, neither of these excitatory amino acids is a substrate for transport. One noticeable exception to the codistribution of the mRNA for rat-XT1 and these excitatory neurotransmitters is the cerebellar Purkinje cell layer, in which GABAergic neurons are localized. The gene encoding for XT1 is localized to the mouse chromosome 3 in the vicinity of the locus for the mouse neurological disorder spastic (spa).     

Genetic and metabolic determinants of nutritional phenotype in an insect-bacterial symbiosis

The pervasive influence of resident microorganisms on the phenotype of their hosts is exemplified by the intracellular bacterium Buchnera aphidicola, which provides its aphid partner with essential amino acids (EAAs). We investigated variation in the dietary requirement for EAAs among four pea aphid (Acyrthosiphon pisum) clones. Buchnera-derived nitrogen contributed to the synthesis of all EAAs for which aphid clones required a dietary supply, and to none of the EAAs for which all four clones had no dietary requirement, suggesting that low total dietary nitrogen may select for reduced synthesis of certain EAAs in some aphid clones. The sequenced Buchnera genomes showed that the EAA nutritional phenotype (i.e. the profile of dietary EAAs required by the aphid) cannot be attributed to sequence variation of Buchnera genes coding EAA biosynthetic enzymes. Metabolic modelling by flux balance analysis demonstrated that EAA output from Buchnera can be determined precisely by the flux of host metabolic precursors to Buchnera. Specifically, the four EAA nutritional phenotypes could be reproduced by metabolic models with unique profiles of host inputs, dominated by variation in supply of aspartate, homocysteine and glutamate. This suggests that the nutritional phenotype of the symbiosis is determined principally by host metabolism and transporter genes that regulate nutrient supply to Buchnera. Intraspecific variation in the nutritional phenotype of symbioses is expected to mediate partitioning of plant resources among aphid genotypes, potentially promoting the genetic subdivision of aphid populations. In this way, microbial symbioses may play an important role in the evolutionary diversification of phytophagous insects.     

The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention

Extracellular concentrations of the predominant excitatory neurotransmitter, glutamate, and related excitatory amino acids are maintained at relatively low levels to ensure an appropriate signal-to-noise ratio and to prevent excessive activation of glutamate receptors that can result in cell death. The latter phenomenon is known as 'excitotoxicity' and has been associated with a wide range of acute and chronic neurodegenerative disorders, as well as disorders that result in the loss of non-neural cells such as oligodendroglia in multiple sclerosis. Unfortunately clinical trials with glutamate receptor antagonists that would logically seem to prevent the effects of excessive receptor activation have been associated with untoward side effects or little clinical benefit. In the mammalian CNS, the extracellular concentrations of glutamate are controlled by two types of transporters; these include a family of Na(+)-dependent transporters and a cystine-glutamate exchange process, referred to as system X(c)(-). In this review, we will focus primarily on the Na(+)-dependent transporters. A brief introduction to glutamate as a neurotransmitter will be followed by an overview of the properties of these transporters, including a summary of the presumed physiologic mechanisms that regulate these transporters. Many studies have provided compelling evidence that impairing the function of these transporters can increase the sensitivity of tissue to deleterious effects of aberrant activation of glutamate receptors. Over the last decade, it has become clear that many neurodegenerative disorders are associated with a change in localization and/or expression of some of the subtypes of these transporters. This would suggest that therapies directed toward enhancing transporter expression might be beneficial. However, there is also evidence that glutamate transporters might increase the susceptibility of tissue to the consequences of insults that result in a collapse of the electrochemical gradients required for normal function such as stroke. In spite of the potential adverse effects of upregulation of glutamate transporters, there is recent evidence that upregulation of one of the glutamate transporters, GLT-1 (also called EAAT2), with beta-lactam antibiotics attenuates the damage observed in models of both acute and chronic neurodegenerative disorders. While it seems somewhat unlikely that antibiotics specifically target GLT-1 expression, these studies identify a potential strategy to limit excitotoxicity. If successful, this type of approach could have widespread utility given the large number of neurodegenerative diseases associated with decreases in transporter expression and excitotoxicity. However, given the massive effort directed at developing glutamate receptor agents during the 1990s and the relatively modest advances to date, one wonders if we will maintain the patience needed to carefully understand the glutamatergic system so that it will be successfully targeted in the future.     

Polymorphisms in large neutral amino acids transporter,system L,in association with CNS disorders

Maintenance of the amino acids (AAs) levels within the central nervous system (CNS) is of importance for the formation of neurotransmitters. Alterations of the l-tryptophan and l-tyrosine (precursors of serotonin and dopamine, respectively) in brain parenchyma may result in serious CNS disorders such as depression. Malfunction of the system L (in particular LAT1/4F2hc) transporter can result in inevitable fluctuation of the large neutral amino acids (NAAs). From our preliminary mutation detection analyses, we hypothesize that the light chain LAT1 (SLC7A5) polymorphisms may change functionality of the system L resulting in fluctuation of key large NAAs levels in CNS. Also, mutations in 4F2hc (SLC3A2), the heavy chain of various AAs transporters, may alter the functions of some key transporters and cause changes in AAs concentrations of the brain. If proven, this hypothesis would grant new insights in molecular biology of the large neutral amino acid transporters in relevance to CNS disorders.     

Motor Axon Synapses on Renshaw Cells Contain Higher Levels of Aspartate than Glutamate

Motoneuron synapses on spinal cord interneurons known as Renshaw cells activate nicotinic, AMPA and NMDA receptors consistent with co-release of acetylcholine and excitatory amino acids (EAA). However, whether these synapses express vesicular glutamate transporters (VGLUTs) capable of accumulating glutamate into synaptic vesicles is controversial. An alternative possibility is that these synapses release other EAAs, like aspartate, not dependent on VGLUTs. To clarify the exact EAA concentrated at motor axon synapses we performed a quantitative postembedding colloidal gold immunoelectron analysis for aspartate and glutamate on motor axon synapses (identified by immunoreactivity to the vesicular acetylcholine transporter; VAChT) contacting calbindin-immunoreactive (-IR) Renshaw cell dendrites. The results show that 71% to 80% of motor axon synaptic boutons on Renshaw cells contained aspartate immunolabeling two standard deviations above average neuropil labeling. Moreover, VAChT-IR synapses on Renshaw cells contained, on average, aspartate immunolabeling at 2.5 to 2.8 times above the average neuropil level. In contrast, glutamate enrichment was lower; 21% to 44% of VAChT-IR synapses showed glutamate-IR two standard deviations above average neuropil labeling and average glutamate immunogold density was 1.7 to 2.0 times the neuropil level. The results were not influenced by antibody affinities because glutamate antibodies detected glutamate-enriched brain homogenates more efficiently than aspartate antibodies detecting aspartate-enriched brain homogenates. Furthermore, synaptic boutons with ultrastructural features of Type I excitatory synapses were always labeled by glutamate antibodies at higher density than motor axon synapses. We conclude that motor axon synapses co-express aspartate and glutamate, but aspartate is concentrated at higher levels than glutamate.     

Excitatory amino acid transporters: keeping up with glutamate

Excitatory amino acid transporters (EAATs) are the primary regulators of extracellular glutamate concentrations in the central nervous system. Among the five known human EAAT subtypes, the glial carriers, EAAT1 and EAAT2 have the greatest impact on clearance of glutamate released during neurotransmission. Studies of carriers expressed on neurons, Purkinje cells and photoreceptor cells (EAAT3, EAAT4 and EAAT5, respectively) suggest more subtle roles for these subtypes in regulating excitability and signalling. The data suggest that EAA transporters may influence glutamatergic transmission by regulating the amount of glutamate available to activate pre- and post-synaptic metabotropic receptors and by altering neuronal excitability through a transporter-associated anion conductance that is activated by carrier substrates. Recent studies on structural, mechanistic and physiological aspects of carrier function in a variety of model systems and organisms have led to surprising insights into how excitatory amino acid transporters shape cellular communication in the nervous system.     

Glutamate Transporters: Expression and Function in Oligodendrocytes

Glutamate, the main excitatory neurotransmitter of the vertebrate central nervous system (CNS), is well known as a regulator of neuronal plasticity and neurodevelopment. Such glutamate function is thought to be mediated primarily by signaling through glutamate receptors. Thus, it requires a tight regulation of extracellular glutamate levels and a fine-tuned homeostasis that, when dysregulated, has been associated with a wide range of central pathologies including neuropsychiatric, neurodevelopmental, and neurodegenerative disorders. In the mammalian CNS, extracellular glutamate levels are controlled by a family of sodium-dependent glutamate transporters belonging to the solute carrier family 1 (SLC1) that are also referred to as excitatory amino acid transporters (EAATs). The presumed main function of EAATs has been best described in the context of synaptic transmission where EAATs expressed by astrocytes and neurons effectively regulate extracellular glutamate levels so that synapses can function independently. There is, however, increasing evidence that EAATs are expressed by cells other than astrocytes and neurons, and that they exhibit functions beyond glutamate clearance. In this review, we will focus on the expression and functions of EAATs in the myelinating cells of the CNS, oligodendrocytes. More specifically, we will discuss potential roles of oligodendrocyte-expressed EAATs in contributing to extracellular glutamate homeostasis, and in regulating oligodendrocyte maturation and CNS myelination by exerting signaling functions that have traditionally been associated with glutamate receptors. In addition, we will provide some examples for how dysregulation of oligodendrocyte-expressed EAATs may be involved in the pathophysiology of neurologic diseases.