title: Interactions of alkali cations with glutamate transporters.
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.
authors.affiliation: Center for Structural and Functional Neuroscience, University of Montana, Missoula, MT 59812, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Holley
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kavanaugh
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D002412:Cations / Q000737:chemistry*; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D043902:Pyrococcus horikoshii / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D027322:Amino Acid Transport System X-AG; D002412:Cations