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Proc Natl Acad Sci U S A
2010 Aug 03;10731:13912-7. doi: 10.1073/pnas.1006289107.
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Evidence for a third sodium-binding site in glutamate transporters suggests an ion/substrate coupling model.
Larsson HP, Wang X, Lev B, Baconguis I, Caplan DA, Vyleta NP, Koch HP, Diez-Sampedro A, Noskov SY.
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Excitatory amino acid transporters (EAATs) remove glutamate from synapses. They maintain an efficient synaptic transmission and prevent glutamate from reaching neurotoxic levels. Glutamate transporters couple the uptake of one glutamate to the cotransport of three sodium ions and one proton and the countertransport of one potassium ion. The molecular mechanism for this coupled uptake of glutamate and its co- and counter-transported ions is not known. In a crystal structure of the bacterial glutamate transporter homolog, GltPh, only two cations are bound to the transporter, and there is no indication of the location of the third sodium site. In experiments using voltage clamp fluorometry and simulations based on molecular dynamics combined with grand canonical Monte Carlo and free energy simulations performed on different isoforms of GltPh as well on a homology model of EAAT3, we sought to locate the third sodium-binding site in EAAT3. Both experiments and computer simulations suggest that T370 and N451 (T314 and N401 in GltPh) form part of the third sodium-binding site. Interestingly, the sodium bound at T370 forms part of the binding site for the amino acid substrate, perhaps explaining both the strict coupling of sodium transport to uptake of glutamate and the ion selectivity of the affinity for the transported amino acid in EAATs.
Borre,
Coupled, but not uncoupled, fluxes in a neuronal glutamate transporter can be activated by lithium ions.
2001, Pubmed
Borre,
Coupled, but not uncoupled, fluxes in a neuronal glutamate transporter can be activated by lithium ions.
2001,
Pubmed Boudker,
Coupling substrate and ion binding to extracellular gate of a sodium-dependent aspartate transporter.
2007,
Pubmed Caplan,
Molecular mechanism of ion-ion and ion-substrate coupling in the Na+-dependent leucine transporter LeuT.
2008,
Pubmed Danbolt,
Glutamate uptake.
2001,
Pubmed Deng,
Computations of standard binding free energies with molecular dynamics simulations.
2009,
Pubmed Grewer,
Individual subunits of the glutamate transporter EAAC1 homotrimer function independently of each other.
2005,
Pubmed Groeneveld,
Na(+):aspartate coupling stoichiometry in the glutamate transporter homologue Glt(Ph).
2010,
Pubmed Grunewald,
Biotinylation of single cysteine mutants of the glutamate transporter GLT-1 from rat brain reveals its unusual topology.
1998,
Pubmed Holley,
Interactions of alkali cations with glutamate transporters.
2009,
Pubmed Kanner,
Binding order of substrates to the sodium and potassium ion coupled L-glutamic acid transporter from rat brain.
1982,
Pubmed Koch,
Small-scale molecular motions accomplish glutamate uptake in human glutamate transporters.
2005,
Pubmed
,
Xenbase Kuang,
TransPath: a computational method for locating ion transit pathways through membrane proteins.
2008,
Pubmed Larsson,
Fluorometric measurements of conformational changes in glutamate transporters.
2004,
Pubmed
,
Xenbase Menaker,
The substrate specificity of a neuronal glutamate transporter is determined by the nature of the coupling ion.
2006,
Pubmed Noskov,
Control of ion selectivity in potassium channels by electrostatic and dynamic properties of carbonyl ligands.
2004,
Pubmed Shrivastava,
Time-resolved mechanism of extracellular gate opening and substrate binding in a glutamate transporter.
2008,
Pubmed Tao,
Neutralization of the aspartic acid residue Asp-367, but not Asp-454, inhibits binding of Na+ to the glutamate-free form and cycling of the glutamate transporter EAAC1.
2006,
Pubmed Tzingounis,
Glutamate transporters: confining runaway excitation by shaping synaptic transmission.
2007,
Pubmed Wadiche,
Kinetics of a human glutamate transporter.
1995,
Pubmed
,
Xenbase Watzke,
Early intermediates in the transport cycle of the neuronal excitatory amino acid carrier EAAC1.
2001,
Pubmed Woo,
Grand canonical Monte Carlo simulations of water in protein environments.
2004,
Pubmed Yamashita,
Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters.
2005,
Pubmed Yernool,
Trimeric subunit stoichiometry of the glutamate transporters from Bacillus caldotenax and Bacillus stearothermophilus.
2003,
Pubmed Yernool,
Structure of a glutamate transporter homologue from Pyrococcus horikoshii.
2004,
Pubmed Zerangue,
Flux coupling in a neuronal glutamate transporter.
1996,
Pubmed
,
Xenbase Zhao,
Evaluations of the Absolute and Relative Free Energies for Antidepressant Binding to the Amino Acid Membrane Transporter LeuT with Free Energy Simulations.
2010,
Pubmed
