Zila Martinez-Lozada
Sandra J. Hewett
Francisco Zafra
Arturo Ortega- 1Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
- 2Program in Neuroscience, Department of Biology, Syracuse University, Syracuse, NY, United States
- 3Center of Molecular Biology Severo Ochoa, School of Science, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
- 4Instituto de Investigación Sanitaria del Hospital Universitario La Paz — IdiPAZ, Madrid, Spain
- 5Department of Toxicology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Mexico
Editorial on the Research Topic
The known, the unknown, and the future of glutamate transporters
Glutamate is the main excitatory neurotransmitter in the central nervous system (Fonnum, 1984). It is required for essentially all cognitive functions, however, is also a neurotoxin. Therefore, maintenance of the glutamate extracellular concentration involves tight control of its release and uptake. Several glutamate transport proteins contribute to this regulation. Vesicular glutamate transporters (VGLUTs) package glutamate into synaptic vesicles (Omote et al., 2011). The excitatory amino acid transporters (EAATs), under physiological conditions, remove glutamate from the synaptic cleft (Danbolt et al., 2016). Lastly, the cystine/glutamate exchanger, also known as system , exports glutamate in exchange for cystine (Jabaudon et al., 1999; Warr et al., 1999; Featherstone and Shippy, 2008). In this Research Topic, we assemble a review of current literature and new research on these transporters.
VGLUTs
Glutamate is packaged into synaptic vesicles via one of three VGLUTs. As part of our collection, Hori and Takamori describe a novel method to monitor glutamate transport in living nerve terminals using the rodent giant synapse, the calyx of Held. In addition, they discuss what is presently known about factors that alter the amount and rate of glutamate refilling of synaptic vesicles and the relevance of these findings to central nervous system disorders (Hori and Takamori).
EAATs
Termination of glutamate signaling is mediated via uptake by one of five EAATs (Hediger et al., 2013). Not surprisingly, impaired expression and/or activity of EAATs have negative repercussions on health. EAAT2 (GLT-1a,b) is predominately expressed by astrocytes, although a small portion of GLT-1a can be found on axon terminals (Chen et al., 2004; Furness et al., 2008; Melone et al., 2009; Zhou et al., 2018).
In this article collection, Yeung et al. examined the expression of EAAT2 in several brain regions from postmortem tissue of patients with Alzheimer's disease (AD) or control (Yeung et al.). The authors found no significant change in EAAT2 density but did observe spatial differences in EAAT2 expression in AD tissue with less immunoreactivity detected in main astrocyte branches, especially on those surrounding neuronal cell bodies (Yeung et al.). Whether this altered expression pattern has implications for glutamate recycling in AD remains to be determined. Direct evidence for pathological loss of function of EAAT2 in a mouse model of Huntington's disease (HD) comes from the paper of Hirschberg et al. Therein they report that abnormal protein-protein interactions of mutant huntingtin (mHTT) with EAAT2 binding partners reduce glutamate uptake in striatal astrocytes and mediate some of the HD-associated deficits studied. Abnormalities in uptake and motor function were alleviated via over-expression of a C-terminal truncated EAAT2 protein (Hirschberg et al.).
Because most of the glutamate clearance (80–90%) is mediated by astrocytic EAAT2/GLT-1, the function of GLT-1 in other cell types has remained largely unexplored. In this collection, two groups report interesting findings concerning the physiological function of GLT-1 in neurons and oligodendrocytes using cell-specific knockout mouse lines. The Rosenberg group found that hippocampal slices prepared from neuronal GLT-1 KO (synGLT-1 KO) mice are more vulnerable to excitotoxicity than slices from wild-type mice (Rimmele et al.). Whether this is due to metabolic compromise, or a disturbance of glutamate homeostasis is still unknown. Meanwhile, the Fuss group reports that deletion of GLT-1 (icKO mice) in maturing oligodendrocytes leads to hypomyelination in the corpus callosum of male, but not female, mice (Thomason et al.). The exact mechanism responsible for these abnormalities is at present unknown.
Finally, the Robinson group used pharmacological inhibition of EAAT function to demonstrate their importance to arteriole patency (Jackson et al.), highlighting another important function of EAATs, which is to act as a bridge between local neuronal activity and increases in blood flow. One can speculate that the dysfunction of EAATs observed in several neuropathologies could negatively affect neurovascular coupling.
It is worth nothing that EAATs not only transport glutamate but act as anion channels (Wadiche et al., 1995; Bergles et al., 2002; Jen et al., 2005). Herein, Kovermann et al. review what is known about this function of the EAATs in both health and disease (Kovermann et al.). For example, they discuss the relationship between EAAT mutations that alter anion channel activity (but not glutamate uptake) resulting in chloride dyshomeostasis and symptoms of neurological disease.
System
System (Sx) is a Na+-independent, Cl− -dependent heteromeric amino acid transporter — formed by two polypeptides, xCT, the subunit responsible for the transport function, and 4F2hc, the subunit required for membrane localization — that functions physiologically to export glutamate while importing cystine in a 1:1 ratio (Bannai and Kitamura, 1980; Bannai, 1986). Astrocytes appear to be the main cell type expressing Sxc- in the mature brain (Zhang et al., 2014; Ottestad-Hansen et al., 2018). Sx activity contributes to the maintenance of redox homeostasis (Banjac et al., 2008), is important for the synthesis of glutathione (Sato et al., 1998), and is a major source of ambient extracellular glutamate in vivo (Baker et al., 2002; De Bundel et al., 2011) However, under pathological conditions, glutamate release through Sx contributes to neurological diseases/disorders [for review see Lewerenz et al. (2013)].
In this article collection, the Hermans group describes and validates a method using tritiated glutamate as a substrate for reversed transport to evaluate the activity of system x (Beckers et al.) both in cultured cells and in synaptosomal preparations. Meanwhile, Bentea et al. investigated the effect of genetic deletion of xCT on two models of Parkinson's disease (PD) (Bentea et al.). They found protection against proteasome inhibition-induced nigrostriatal degeneration, — but not MPTP-induced striatal toxicity — in xCT−/− mice. Last but not least, He and Hewett evaluated the contribution of Sx to ischemic stroke (He and Hewett). Their results demonstrate that Sx contributes to cortical ischemic damage when blood flow is moderately but not severely reduced.
Altogether, in this Research Topic, the authors review current literature or provide original research centered on understanding more fully the physiological and/or pathophysiological function of glutamate transport. The work presented here highlights the need for further research on the myriad of roles glutamate transporters play in health and pathology. Therefore, we hope that this collection encourages additional research in this field.
Author contributions
ZM-L produced the initial draft. SH, FZ, and AO further edited and provided additional content and references. All authors approved the final version for publication.
Acknowledgments
We want to thank all the authors of this Research Topic for their contributions, and the reviewers for their insightful comments that helped maintain the articles at the highest standards.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
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References
Baker, D. A., Xi, Z. X., Shen, H., Swanson, C. J., and Kalivas, P. W. (2002). The origin and neuronal function of in vivo nonsynaptic glutamate. J. Neurosci. 22, 9134–9141. doi: 10.1523/JNEUROSCI.22-20-09134.2002
Banjac, A., Perisic, T., Sato, H., Seiler, A., Bannai, S., Weiss, N., et al. (2008). The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death. Oncogene 27, 1618–1628. doi: 10.1038/sj.onc.1210796
Bannai, S. (1986). Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J. Biol. Chem. 261, 2256–2263. doi: 10.1016/S0021-9258(17)35926-4
Bannai, S., and Kitamura, E. (1980). Transport interaction of L-cystine and L-glutamate in human diploid fibroblasts in culture. J. Biol. Chem. 255, 2372–2376. doi: 10.1016/S0021-9258(19)85901-X
Bergles, D. E., Tzingounis, A. V., and Jahr, C. E. (2002). Comparison of coupled and uncoupled currents during glutamate uptake by GLT-1 transporters. J. Neurosci. 22, 10153–10162. doi: 10.1523/JNEUROSCI.22-23-10153.2002
Chen, W., Mahadomrongkul, V., Berger, U. V., Bassan, M., DeSilva, T., Tanaka, K., et al. (2004). The glutamate transporter GLT1a is expressed in excitatory axon terminals of mature hippocampal neurons. J. Neurosci. 24, 1136–1148. doi: 10.1523/JNEUROSCI.1586-03.2004
Danbolt, N., Furness, D., and Zhou, Y. (2016). Neuronal vs glial glutamate uptake: resolving the conundrum. Neurochem. Int. 98, 29–45. doi: 10.1016/j.neuint.2016.05.009
De Bundel, D., Schallier, A., Loyens, E., Fernando, R., Miyashita, H., Van Liefferinge, J., et al. (2011). Loss of system xc- does not induce oxidative stress but decreases extracellular glutamate in hippocampus and influences spatial working memory and limbic seizure susceptibility. J. Neurosci. 31, 5792–5803. doi: 10.1523/JNEUROSCI.5465-10.2011
Featherstone, D. E., and Shippy, S. A. (2008). Regulation of synaptic transmission by ambient extracellular glutamate. Neuroscientist 14, 171–181. doi: 10.1177/1073858407308518
Fonnum, F. (1984). Glutamate: a neurotransmitter in mammalian brain. J. Neurochem. 42, 1–11. doi: 10.1111/j.1471-4159.1984.tb09689.x
Furness, D., Dehnes, Y., Akhtar, A., Rossi, D., Hamann, M., Grutle, N., et al. (2008). A quantitative assessment of glutamate uptake into hippocampal synaptic terminals and astrocytes: new insights into a neuronal role for excitatory amino acid transporter 2 (EAAT2). Neuroscience 157, 80–94. doi: 10.1016/j.neuroscience.2008.08.043
Hediger, M. A., Clémençon, B., Burrier, R. E., and Bruford, E. A. (2013). The ABCs of membrane transporters in health and disease (SLC series): introduction. Molec. Aspects Med. 34, 95–107. doi: 10.1016/j.mam.2012.12.009
Jabaudon, D., Shimamoto, K., Yasuda-Kamatani, Y., Scanziani, M., Gahwiler, B. H., and Gerber, U. (1999). Inhibition of uptake unmasks rapid extracellular turnover of glutamate of nonvesicular origin. Proc. Natl. Acad. Sci. U S A. 96, 8733–8738. doi: 10.1073/pnas.96.15.8733
Jen, J. C., Wan, J., Palos, T. P., Howard, B. D., and Baloh, R. W. (2005). Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 65, 529–534. doi: 10.1212/01.WNL.0000172638.58172.5a
Lewerenz, J., Hewett, S. J., Huang, Y., Lambros, M., Gout, P. W., Kalivas, P. W., et al. (2013). The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signal 18, 522–555. doi: 10.1089/ars.2011.4391
Melone, M., Bellesi, M., and Conti, F. (2009). Synaptic localization of GLT-1a in the rat somatic sensory cortex. Glia 57, 108–117. doi: 10.1002/glia.20744
Omote, H., Miyaji, T., Juge, N., and Moriyama, Y. (2011). Vesicular neurotransmitter transporter: bioenergetics and regulation of glutamate transport. Biochemistry 50, 5558–5565. doi: 10.1021/bi200567k
Ottestad-Hansen, S., Hu, Q. X., Follin-Arbelet, V. V., Bentea, E., Sato, H., Massie, A., et al. (2018). The cystine-glutamate exchanger (xCT, Slc7a11) is expressed in significant concentrations in a subpopulation of astrocytes in the mouse brain. Glia 66, 951–970. doi: 10.1002/glia.23294
Sato Kuriyama-Matsumura, K., Siow, R., Ishii, T., Bannai, S., and Mann, G. E. (1998). Induction of cystine transport via system xc– and maintenance of intracellular glutathione levels in pancreatic acinar and islet cell lines. Biochim. Biophys. Acta (BBA)-Biomembranes 1414, 85–94. doi: 10.1016/S0005-2736(98)00159-X
Wadiche, J. I., Arriza, J. L., Amara, S. G., and Kavanaugh, M. P. (1995). Kinetics of a human glutamate transporter. Neuron 14, 1019–1027. doi: 10.1016/0896-6273(95)90340-2
Warr, O., Takahashi, M., and Attwell, D. (1999). Modulation of extracellular glutamate concentration in rat brain slices by cystine-glutamate exchange. J. Physiol. 514, 783–793. doi: 10.1111/j.1469-7793.1999.783ad.x
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., et al. (2014). An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947. doi: 10.1523/JNEUROSCI.1860-14.2014
Keywords: glutamate, glutamate transport, excitatory amino acid transporter (EAAT), vesicular glutamate transport proteins, system
Citation: Martinez-Lozada Z, Hewett SJ, Zafra F and Ortega A (2022) Editorial: The known, the unknown, and the future of glutamate transporters. Front. Cell. Neurosci. 16:1005834. doi: 10.3389/fncel.2022.1005834
Received: 28 July 2022; Accepted: 04 August 2022;
Published: 17 August 2022.
Edited and reviewed by: Enrico Cherubini, European Brain Research Institute, Italy
Copyright © 2022 Martinez-Lozada, Hewett, Zafra and Ortega. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zila Martinez-Lozada, martinezlz@chop.edu