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@ARTICLE{Kolen:884257,
      author       = {Kolen, Bettina and Kortzak, Daniel and Franzen, Arne and
                      Fahlke, Christoph},
      title        = {{A}n amino-terminal point mutation increases {EAAT}2 anion
                      currents without affecting glutamate transport rates},
      journal      = {The journal of biological chemistry},
      volume       = {295},
      number       = {44},
      issn         = {1083-351X},
      address      = {Bethesda, Md.},
      publisher    = {Soc.72889},
      reportid     = {FZJ-2020-03152},
      pages        = {14936-14947},
      year         = {2020},
      abstract     = {Excitatory amino acid transporters (EAATs) are prototypical
                      dual function proteins that function as coupled
                      glutamate/Na+/H+/K+ transporters and as anion-selective
                      channels. Both transport functions are intimately
                      intertwined at the structural level: Secondary active
                      glutamate transport is based on elevator-like movements of
                      the mobile transport domain across the membrane, and the
                      lateral movement of this domain results in anion channel
                      opening. This particular anion channel gating mechanism
                      predicts the existence of mutant transporters with changed
                      anion channel properties, but without alteration in
                      glutamate transport. We here report that the L46P mutation
                      in the human EAAT2 transporter fulfills this prediction. L46
                      is a pore-forming residue of the EAAT2 anion channels at the
                      cytoplasmic entrance into the ion conduction pathway. In
                      whole-cell patch clamp recordings, we observed larger
                      macroscopic anion current amplitudes for L46P than for WT
                      EAAT2. Rapid l-glutamate application under forward transport
                      conditions demonstrated that L46P does not reduce the
                      transport rate of individual transporters. In contrast,
                      changes in selectivity made gluconate permeant in L46P
                      EAAT2, and nonstationary noise analysis revealed slightly
                      increased unitary current amplitudes in mutant EAAT2 anion
                      channels. We used unitary current amplitudes and individual
                      transport rates to quantify absolute open probabilities of
                      EAAT2 anion channels from ratios of anion currents by
                      glutamate uptake currents. This analysis revealed up to
                      7-fold increased absolute open probability of L46P EAAT2
                      anion channels. Our results reveal an important determinant
                      of the diameter of EAAT2 anion pore and demonstrate the
                      existence of anion channel gating processes outside the EAAT
                      uptake cycle.},
      cin          = {IBI-1},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IBI-1-20200312},
      pnm          = {552 - Engineering Cell Function (POF3-552)},
      pid          = {G:(DE-HGF)POF3-552},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {32820048},
      UT           = {WOS:000588414100012},
      doi          = {10.1074/jbc.RA120.013704},
      url          = {https://juser.fz-juelich.de/record/884257},
}