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@ARTICLE{Borghans:1044114,
      author       = {Borghans, Bart and Kortzak, Daniel and Longo, Piersilvio
                      and Kolen, Bettina and Machtens, Jan-Philipp and Fahlke,
                      Christoph},
      title        = {{A}llosteric modulation of proton binding confers {C}l-
                      activation and glutamate selectivity to vesicular glutamate
                      transporters},
      journal      = {PLoS Computational Biology},
      volume       = {21},
      number       = {6},
      issn         = {1553-734X},
      address      = {San Francisco, Calif.},
      publisher    = {Public Library of Science},
      reportid     = {FZJ-2025-03030},
      pages        = {e1013214 -},
      year         = {2025},
      abstract     = {Vesicular glutamate transporters (VGLUTs) fill synaptic
                      vesicles with glutamate andremove luminal Cl- via an
                      additional anion channel mode. Both of these
                      transportfunctions are stimulated by luminal acidification,
                      luminal-positive membrane potential,and luminal Cl-. We
                      studied VGLUT1 transporter/channel activation using
                      acombination of heterologous expression, cellular
                      electrophysiology, fast solutionexchange, and mathematical
                      modeling. Cl- channel gating can be described with akinetic
                      scheme that includes two protonation sites and distinct
                      opening, closing, andCl--binding rates for each protonation
                      state. Cl- binding promotes channel openingby modifying the
                      pKa values of the protonation sites and rates of pore
                      opening andclosure. VGLUT1 transports glutamate and
                      aspartate at distinct stoichiometries:H+-glutamate exchange
                      at 1:1 stoichiometry and aspartate uniport.
                      Neurotransmittertransport with variable stoichiometry can be
                      described with an alternating accessmodel that assumes that
                      transporters without substrate translocate in the doubly
                      protonatedstate to the inward-facing conformation and return
                      with the bound amino acidsubstrate as either singly or
                      doubly protonated. Glutamate, but not aspartate, promotesthe
                      release of one proton from inward-facing VGLUT1, resulting
                      in preferentialH+-coupled glutamate exchange. Cl- stimulates
                      glutamate transport by making theglutamate-binding site
                      accessible to cytoplasmic glutamate and by facilitating
                      transitionsto the inward-facing conformation after outward
                      substrate release. We concludethat allosteric modification
                      of transporter protonation by Cl- is crucial for both
                      VGLUT1transport functions.},
      cin          = {IBI-1},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-1-20200312},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524) / 5244 - Information Processing in Neuronal
                      Networks (POF4-524) / DFG project G:(GEPRIS)291198853 - FOR
                      2518: Funktionale Dynamik von Ionenkanälen und Transportern
                      - DynIon - (291198853) / DFG project G:(GEPRIS)394431587 -
                      FOR 2795: Synapsen unter Stress: akute Veränderungen durch
                      mangelnde Energiezufuhr an glutamatergen Synapsen
                      (394431587)},
      pid          = {G:(DE-HGF)POF4-5241 / G:(DE-HGF)POF4-5244 /
                      G:(GEPRIS)291198853 / G:(GEPRIS)394431587},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1371/journal.pcbi.1013214},
      url          = {https://juser.fz-juelich.de/record/1044114},
}