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  • Review Article
  • Published:

Glutamate transporters: confining runaway excitation by shaping synaptic transmission

Nature Reviews Neuroscience volume 8, pages 935–947 (2007)Cite this article

Key Points

  • Excitatory amino-acid transporters (EAATs) terminate glutamate's actions and thus maintain proper neuronal function. These proteins are expressed in vast quantities by glia, but are also present in neurons.

  • Glutamate uptake is coupled to the cotransport of three Na+ ions and one H+ ion, and the countertransport of one K+ ion. This stoichiometry is responsible for keeping the tonic extracellular glutamate concentration at ∼25 nM: below that which is required to significantly activate receptors.

  • In addition to the coupled ions, glutamate transporters allow an uncoupled anion flux. This anion conductance is thought to reflect the occupancy of glutamate-bound conformations, and allows the direct measurement of the activity of transporters.

  • The affinity constants measured from peak currents of neuronal transporters predict that they behave as buffers to rapidly bind released glutamate molecules, whereas the affinities of the more numerous glial transporters predict that they act also as sinks, removing glutamate from the extracellular space.

  • At Schaeffer collateral–CA1 synapses in the hippocampus, glial transporters are responsible for taking up more than 80% of the released glutamate, whereas the neuronal transporters limit spillover between synapses.

  • In the cerebellum, like in the hippocampus, glial transporters are responsible for the bulk of glutamate uptake, whereas the neuronal transporter EAAT4, which is found exclusively in Purkinje cells, regulates extrasynaptic receptor activation and subsequent cerebellar plasticity.

  • At retinal synapses, unlike in any other brain region, presynaptic glutamate transporters act as Cl− channels, rather than transporters, to reduce vesicular release at individual boutons.

  • The high concentration of EAATs around synapses ensures that unbound glutamate will encounter available transporters. Together, rapid sequestration, low capture efficiency and the high concentration of EAATs lead to the buffered diffusion of glutamate, which prevents it spilling back into the synapse.

Abstract

Traditionally, glutamate transporters have been viewed as membrane proteins that harness the electrochemical gradient to slowly transport glutamate from the extracellular space into glial cells. However, recent studies have shown that glutamate transporters on glial and neuronal membranes also rapidly bind released glutamate to shape synaptic transmission. In this Review, we summarize the properties of glutamate transporters that influence synaptic transmission and are subject to regulation and plasticity. We highlight how the diversity of glutamate-transporter function relates to transporter location, density and affinity.

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Figure 1: Uptake thermodynamics of glutamate transporters.
Figure 2: The crystal structure of a bacterial glutamate transporter.
Figure 3: The architecture of hippocampal CA1 synapses.
Figure 4: The architecture of cerebellar Purkinje-cell synapses.
Figure 5: The architecture of retinal synapses.

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Acknowledgements

We would like to thank J. Diamond, C. Jahr, M. Kavanaugh and K. Matsui for discussions and K. Menuz and members of the Wadiche labs for discussions and comments on the manuscript. We would also like to thank S. Rudolph for providing the original artwork for figures 3, 4 and 5 and boxes 1 and 2. Finally, we would like to especially thank L. O. Wadiche for her help and comments.

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, 94107, California, USA

    Anastassios V. Tzingounis

  2. Department of Neurobiology and McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Jacques I. Wadiche

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  1. Anastassios V. Tzingounis
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  2. Jacques I. Wadiche
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Correspondence to Jacques I. Wadiche.

Supplementary information

Supplementary information S1 (Box)

Glutamate transporter affinity constants (PDF 114 kb)

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Glossary

Reversal potential

The membrane potential when there is no net flow of ions across the membrane. Current flows in opposite directions above and below the reversal potential.

Zero-flux equation

An equation that defines the thermodynamic equilibrium membrane potential when the influx of glutamate to the cytosol equals the efflux of glutamate to the extracellular space.

Fluorescence resonance energy transfer

(FRET). Also known as Förster resonance energy transfer. A spectroscopic technique that uses the direct transfer of energy from one fluorophore to another to measure the distance between the fluorophores.

Electrogenic process

A process that produces a net charge movement across the membrane electric field.

Cycling rate

The recovery time of the peak transporter current, measured using a paired-pulse application protocol. It defines the maximum rate at which a transporter will become available to bind a second molecule of glutamate, regardless of whether the first molecule is transported or unbound outside.

Turnover rate

The rate at which a transporter binds glutamate, transports it and then becomes available for another transport cycle.

Capture efficiency

The probability that a glutamate molecule bound to a transporter will be transported into the cytosol rather than be unbound back into the extracellular space.

Excitatory postsynaptic current (EPSC)

The current through the excitatory synaptic conductance, as recorded in voltage clamp. In current clamp, the current through this conductance results in an excitatory postsynaptic potential — that is, it depolarizes the neuron.

Field stimulation

Synchronous activation of a population of neurons.

Synaptic transporter currents

(STCs). Glutamate transporter currents that are obtained in either glia or neurons in response to synaptic stimulation.

Heteroexchange

The process by which an inwardly transported substrate leads to the efflux of another substrate by the same transporter.

Zebrin II

A brain-specific glycolytic isoenzyme, also known as aldolase C, that exemplifies the heterogeneity of Purkinje cells.

Shunting inhibition

A conductance change that inhibits further activity because more current is required to change the membrane potential.

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Tzingounis, A., Wadiche, J. Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nat Rev Neurosci 8, 935–947 (2007). https://doi.org/10.1038/nrn2274

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