Document Type

Article

Publication Title

Philosophical Transactions of the Royal Society B

Publisher

The Royal Society

Publication Date

1-2009

Volume

364

Issue

1514

Disciplines

Medical Sciences | Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

Abstract

The transport of glutamate is coupled to the co-transport of three Na+ ions and the countertransport of one K+ ion. In addition to this carrier-type exchange behaviour, glutamate transporters also behave as chloride channels. The chloride channel activity is strongly influenced by the cations that are involved in coupled flux, making glutamate transporters representative of the ambiguous interface between carriers and channels. In this paper, we review the interaction of alkali cations with glutamate transporters in terms of these diverse functions. We also present a model derived from electrostatic mapping of the predicted cation-binding sites in the X-ray crystal structure of the Pyrococcus horikoshii transporter GltPh and in its human glutamate transporter homologue EAAT3. Two predicted Na+-binding sites were found to overlap precisely with the Tl+ densities observed in the aspartate-bound complex. A novel third site predicted to favourably bind Na+ (but not Tl+) is formed by interaction with the substrate and the occluding HP2 loop. A fourth predicted site in the apo state exhibits selectivity for K+ over both Na+ and Tl+. Notably, this K+ site partially overlaps the glutamate-binding site, and their binding is mutually exclusive. These results are consistent with kinetic and structural data and suggest a plausible mechanism for the flux coupling of glutamate with Na+ and K+ ions.

Keywords

glutamate transporter, chloride channel, ion binding, synaptic transmission

DOI

10.1098/rstb.2008.0246

Rights

Copyright - 2008 The Royal Society

Creative Commons License

Creative Commons Attribution 3.0 License
This work is licensed under a Creative Commons Attribution 3.0 License.

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