Molecular and cellular physiology of sodium-dependent glutamate transporters

doi:10.1016/j.brainresbull.2016.12.013

Brain Research Bulletin

Volume 136, January 2018, Pages 3-16

https://doi.org/10.1016/j.brainresbull.2016.12.013 Get rights and content

Highlights

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Glial glutamate transporters mediate the majority of glutamate uptake in the brain.
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EAATs are dual function transport proteins and also serve as anion channels.
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EAATs shape glutamatergic transmission and protect from excitotoxicity.

Abstract

Glutamate is the major excitatory transmitter in the vertebrate brain. After its release from presynaptic nerve terminals, it is rapidly taken up by high-affinity sodium-dependent plasma membrane transporters. While both neurons and glial cells express these excitatory amino acid transporters (EAATs), the majority of glutamate uptake is accomplished by astrocytes, which convert synaptically-released glutamate to glutamine or feed it into their own metabolism. Glutamate uptake by astrocytes not only shapes synaptic transmission by regulating the availability of glutamate to postsynaptic neuronal receptors, but also protects neurons from hyper-excitability and subsequent excitotoxic damage. In the present review, we provide an overview of the molecular and cellular characteristics of sodium-dependent glutamate transporters and their associated anion permeation pathways, with a focus on astrocytic glutamate transport. We summarize their functional properties and roles within tripartite synapses under physiological and pathophysiological conditions, exemplifying the intricate interactions and interrelationships between neurons and glial cells in the brain.

Graphical abstract

Introduction

Glutamatergic synapses are the most prevalent excitatory synapses in the central nervous system (CNS). The glutamate released at the synapses is taken up by neurons and astrocytes via sodium-dependent glutamate transporters, also termed excitatory amino acid transporters (EAATs) (Nicholls and Attwell, 1990, Anderson and Swanson, 2000, Maragakis and Rothstein, 2001, Schousboe, 2003; Fig. 1A). Astrocytes take up the majority of released glutamate, and astrocytic glutamate transport is vital for proper performance of both the mature and the developing CNS (Rothstein et al., 1996, Tanaka et al., 1997, Matsugami et al., 2006, Petr et al., 2015). Up to now, five transporter subtypes (EAAT 1-5) have been identified and cloned from mammalian tissues, with astrocytes mainly expressing EAAT1 and EAAT2 (Danbolt, 2001). The isoforms share many common structural and molecular properties; but they differ in functional characteristics such as glutamate transport rates and substrate affinities (Vandenberg and Ryan, 2013, Fahlke et al., 2016).

EAAT glutamate uptake is driven by the co-transport of three sodium ions and one proton, as well as the counter-transport of one potassium ion (Fig. 1B). This complex stoichiometry frees up enough energy to permit active transport of glutamate into the cell against a steep concentration gradient. Additionally it ensures that glutamate transport only reverses under extreme conditions (Szatkowski and Attwell, 1994). For various pathological situations, acute or chronic reduction in overall glial glutamate uptake capacity contributes to increased extracellular glutamate concentrations and results in excitotoxicity (Allaman et al., 2011). Glutamate uptake by astrocytes thus not only shapes synaptic transmission by regulating the availability of glutamate to postsynaptic neuronal receptors, but also protects neurons from hyper-excitability and excitotoxic damage. The present review will focus on discussing the molecular and cellular physiology of glial sodium-dependent glutamate transporters, which are mediators of complex interactions and inter-dependence between neurons and astrocytes in the brain.

Section snippets

Glutamate transporter isoforms

The molecular characterization of neuronal and glial glutamate transporters started with the biochemical characterization and purification of such proteins from the mammalian brain. These early studies permitted a functional characterization of the transport properties of glutamate transporters (Kanner and Sharon, 1978, Kanner and Bendahan, 1982, Kanner and Marva, 1982, Pines and Kanner, 1990) and were instrumental for the molecular characterization of mammalian EAATs (Kanai and Hediger, 1992,

EAAT expression profiles

The five mammalian EAAT isoforms exhibit distinct localizations in the mammalian brain. Two are mainly expressed in glia (EAAT1 and EAAT2; Storck et al., 1992, Chaudhry et al., 1995, Lehre and Danbolt, 1998), whereas EAAT3, EAAT4 and EAAT5 are predominantly found in neuronal cells (Dehnes et al., 1998, Sullivan et al., 2004, Holmseth et al., 2012). EAAT2 represents the major isoform responsible for glutamate clearance in the brain (Tanaka et al., 1997). It is not only expressed in glia, but can

Conclusion

In recent years, great progress has been made in understanding sodium-dependent glutamate transporters and their associated anion channels in the human brain. Genes encoding sodium-dependent glutamate transporters were identified, and heterologous expression permitted detailed insights into the function of these proteins. Crystallization of prokaryotic homologues clarified the architecture of these proteins and allowed computer based molecular dynamics simulation of multiple transport

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

We thank Lisa Felix, Institute of Neurobiology, for critical comments on the manuscript and Dr. Jan-Philipp Machtens, Institute of Complex Systems, for helpful discussion and providing figures 2 and 3. This work was supported by the German Research Foundation (Ro2327/8-1).

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Research reportMolecular and cellular physiology of sodium-dependent glutamate transporters

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Glutamate transporter isoforms

EAAT expression profiles

Conclusion

Conflict of interest

Acknowledgements

Biochem. Pharmacol.

Trends Neurosci.

J. Biol. Chem.

Neuron

Neuron

Trends Neurosci.

J. Biol. Chem.

Neuron

Curr. Opin. Neurobiol.

Neuron

J. Biol. Chem.

Biochem. Pharmacol.

Neurochem. Int.

Brain Res.

Neuron

Cell

Neuropharmacology

J. Biol. Chem.

Prog. Neurobiol.

Brain Res. Rev.

Biophys. J.

Prog. Brain Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Dev. Biol.

Neuron

J. Biol. Chem.

Curr. Opin. Neurobiol.

Allosteric modulation of an excitatory amino acid transporter: the subtype-selective inhibitor UCPH-101 exerts sustained inhibition of EAAT1 through an intramonomeric site in the trimerization domain

J. Neurosci.

Genetic and functional studies of a missense variant in a glutamate transporter, SLC1A3, in Tourette syndrome

Psychiatr. Genet.

Neuronal activity mediated regulation of glutamate transporter GLT-1 surface diffusion in rat astrocytes in dissociated and slice cultures

Glia

Intracellular pH changes produced by glutamate uptake in rat hippocampal slices

J. Neurophysiol.

Astrocyte glutamate transport: review of properties, regulation, and physiological functions

Glia

Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse

Nat. Neurosci.

Cooperation between independent hippocampal synapses is controlled by glutamate uptake

Nat. Neurosci.

Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex

J. Neurosci.

Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance

Proc. Natl. Acad. Sci. U. S. A.

Glutamate transport decreases mitochondrial pH and modulates oxidative metabolism in astrocytes

J. Neurosci.

The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer

J. Neurochem.

Electrogenic glutamate uptake in glial cells is activated by intracellular potassium

Nature

Electrogenic uptake of glutamate and aspartate into glial cells isolated from the salamander (Ambystoma) retina

J. Physiol.

Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement

Br. J. Pharmacol.

Short-term plasticity of Bergmann glial cell extrasynaptic currents during parallel fiber stimulation in rat cerebellum

Glia

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Glia

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Proc. Natl. Acad. Sci. U. S. A.

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J. Neurosci.

Research report
Molecular and cellular physiology of sodium-dependent glutamate transporters