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Glutamate Transporters and Mitochondria: Signaling, Co-compartmentalization, Functional Coupling, and Future Directions

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Abstract

In addition to being an amino acid that is incorporated into proteins, glutamate is the most abundant neurotransmitter in the mammalian CNS, the precursor for the inhibitory neurotransmitter γ-aminobutyric acid, and one metabolic step from the tricarboxylic acid cycle intermediate α-ketoglutarate. Extracellular glutamate is cleared by a family of Na+-dependent transporters. These transporters are variably expressed by all cell types in the nervous system, but the bulk of clearance is into astrocytes. GLT-1 and GLAST (also called EAAT2 and EAAT1) mediate this activity and are extremely abundant proteins with their expression enriched in fine astrocyte processes. In this review, we will focus on three topics related to these astrocytic glutamate transporters. First, these transporters co-transport three Na+ ions and a H+ with each molecule of glutamate and counter-transport one K+; they are also coupled to a Cl− conductance. The movement of Na+ is sufficient to cause profound astrocytic depolarization, and the movement of H+ is linked to astrocytic acidification. In addition, the movement of Na+ can trigger the activation of Na+ co-transporters (e.g. Na+–Ca2+ exchangers). We will describe the ways in which these ionic movements have been linked as signals to brain function and/or metabolism. Second, these transporters co-compartmentalize with mitochondria, potentially providing a mechanism to supply glutamate to mitochondria as a source of fuel for the brain. We will provide an overview of the proteins involved, discuss the evidence that glutamate is oxidized, and then highlight some of the un-resolved issues related to glutamate oxidation. Finally, we will review evidence that ischemic insults (stroke or oxygen/glucose deprivation) cause changes in these astrocytic mitochondria and discuss the ways in which these changes have been linked to glutamate transport, glutamate transport-dependent signaling, and altered glutamate metabolism. We conclude with a broader summary of some of the unresolved issues.

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Acknowledgements

The authors regret that we were not able to cite all of the numerous studies that have been published in this area. The authors are partially supported by a grant from the National Institutes of Neurologic Disorders and Stroke of the National Institutes of Health (R01 NS106693). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Departments of Pediatrics and Systems Pharmacology & Translational Therapeutics, Children’s Hospital of Philadelphia, University of Pennsylvania, 502N, Abramson Pediatric Research Building, 3615 Civic Center Boulevard, Philadelphia, PA, 19104-4318, USA

    Michael B. Robinson, Meredith L. Lee & Sabrina DaSilva

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Robinson, M.B., Lee, M.L. & DaSilva, S. Glutamate Transporters and Mitochondria: Signaling, Co-compartmentalization, Functional Coupling, and Future Directions. Neurochem Res 45, 526–540 (2020). https://doi.org/10.1007/s11064-020-02974-8

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