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Allosteric gate modulation confers K(+) coupling in glutamate transporters

Excitatory amino acid transporters (EAATs) mediate glial and neuronal glutamate uptake to terminate synaptic transmission and to ensure low resting glutamate concentrations. Effective glutamate uptake is achieved by cotransport with 3 Na(+) and 1 H(+), in exchange with 1 K(+). The underlying princip...

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Autores principales: Kortzak, Daniel, Alleva, Claudia, Weyand, Ingo, Ewers, David, Zimmermann, Meike I, Franzen, Arne, Machtens, Jan‐Philipp, Fahlke, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769379/
https://www.ncbi.nlm.nih.gov/pubmed/31506973
http://dx.doi.org/10.15252/embj.2019101468
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author Kortzak, Daniel
Alleva, Claudia
Weyand, Ingo
Ewers, David
Zimmermann, Meike I
Franzen, Arne
Machtens, Jan‐Philipp
Fahlke, Christoph
author_facet Kortzak, Daniel
Alleva, Claudia
Weyand, Ingo
Ewers, David
Zimmermann, Meike I
Franzen, Arne
Machtens, Jan‐Philipp
Fahlke, Christoph
author_sort Kortzak, Daniel
collection PubMed
description Excitatory amino acid transporters (EAATs) mediate glial and neuronal glutamate uptake to terminate synaptic transmission and to ensure low resting glutamate concentrations. Effective glutamate uptake is achieved by cotransport with 3 Na(+) and 1 H(+), in exchange with 1 K(+). The underlying principles of this complex transport stoichiometry remain poorly understood. We use molecular dynamics simulations and electrophysiological experiments to elucidate how mammalian EAATs harness K(+) gradients, unlike their K(+)‐independent prokaryotic homologues. Glutamate transport is achieved via elevator‐like translocation of the transport domain. In EAATs, glutamate‐free re‐translocation is prevented by an external gate remaining open until K(+) binding closes and locks the gate. Prokaryotic Glt(Ph) contains the same K(+)‐binding site, but the gate can close without K(+). Our study provides a comprehensive description of K(+)‐dependent glutamate transport and reveals a hitherto unknown allosteric coupling mechanism that permits adaptions of the transport stoichiometry without affecting ion or substrate binding.
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spelling pubmed-67693792019-10-03 Allosteric gate modulation confers K(+) coupling in glutamate transporters Kortzak, Daniel Alleva, Claudia Weyand, Ingo Ewers, David Zimmermann, Meike I Franzen, Arne Machtens, Jan‐Philipp Fahlke, Christoph EMBO J Articles Excitatory amino acid transporters (EAATs) mediate glial and neuronal glutamate uptake to terminate synaptic transmission and to ensure low resting glutamate concentrations. Effective glutamate uptake is achieved by cotransport with 3 Na(+) and 1 H(+), in exchange with 1 K(+). The underlying principles of this complex transport stoichiometry remain poorly understood. We use molecular dynamics simulations and electrophysiological experiments to elucidate how mammalian EAATs harness K(+) gradients, unlike their K(+)‐independent prokaryotic homologues. Glutamate transport is achieved via elevator‐like translocation of the transport domain. In EAATs, glutamate‐free re‐translocation is prevented by an external gate remaining open until K(+) binding closes and locks the gate. Prokaryotic Glt(Ph) contains the same K(+)‐binding site, but the gate can close without K(+). Our study provides a comprehensive description of K(+)‐dependent glutamate transport and reveals a hitherto unknown allosteric coupling mechanism that permits adaptions of the transport stoichiometry without affecting ion or substrate binding. John Wiley and Sons Inc. 2019-09-10 2019-10-01 /pmc/articles/PMC6769379/ /pubmed/31506973 http://dx.doi.org/10.15252/embj.2019101468 Text en © 2019 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Kortzak, Daniel
Alleva, Claudia
Weyand, Ingo
Ewers, David
Zimmermann, Meike I
Franzen, Arne
Machtens, Jan‐Philipp
Fahlke, Christoph
Allosteric gate modulation confers K(+) coupling in glutamate transporters
title Allosteric gate modulation confers K(+) coupling in glutamate transporters
title_full Allosteric gate modulation confers K(+) coupling in glutamate transporters
title_fullStr Allosteric gate modulation confers K(+) coupling in glutamate transporters
title_full_unstemmed Allosteric gate modulation confers K(+) coupling in glutamate transporters
title_short Allosteric gate modulation confers K(+) coupling in glutamate transporters
title_sort allosteric gate modulation confers k(+) coupling in glutamate transporters
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769379/
https://www.ncbi.nlm.nih.gov/pubmed/31506973
http://dx.doi.org/10.15252/embj.2019101468
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