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

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Abstract

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.

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Acknowledgements

The authors thank Dr. Georg Nagel for critical reading of the manuscript and helpful comments. This work was supported by the National Institutes of Health Grant R01-NS0493 to CG and by the Deutsche Forschungsgemeinschaft Grants GR 1393/2-2,3 to CG and RA 753/1-1,2 to TR. CG and TR are also grateful for support by the Max-Planck-Institute for Biophysics and Brain Research, respectively.

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  1. Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, FL, 33136, USA

    C. Grewer

  2. Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Münster, D 48149 , Germany

    T. Rauen

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  1. C. Grewer
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Grewer, C., Rauen, T. Electrogenic Glutamate Transporters in the CNS: Molecular Mechanism, Pre-steady-state Kinetics, and their Impact on Synaptic Signaling. J Membrane Biol 203, 1–20 (2005). https://doi.org/10.1007/s00232-004-0731-6

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