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@ARTICLE{Kovermann:904700,
      author       = {Kovermann, Peter and Kolobkova, Yulia and Franzen, Arne and
                      Fahlke, Christoph},
      title        = {{M}utations associated with epileptic encephalopathy modify
                      {EAAT}2 anion channel function},
      journal      = {Epilepsia},
      volume       = {63},
      number       = {2},
      issn         = {0013-9580},
      address      = {Oxford [u.a.]},
      publisher    = {Wiley-Blackwell},
      reportid     = {FZJ-2022-00049},
      pages        = {388-401},
      year         = {2022},
      note         = {Funding information: German Ministry of Education and
                      Research, Grant Number: 01GM19007Early View: Onlinefirst},
      abstract     = {ObjectiveMutations in the gene solute carrier family member
                      1A2 (SLC1A2) encoding the excitatory amino acid transporter
                      2 (EAAT2) are associated with severe forms of epileptic
                      encephalopathy. EAAT2 is expressed in glial cells and
                      presynaptic nerve terminals and represents the main
                      l-glutamate uptake carrier in the mammalian brain. It does
                      not only function as a secondary active glutamate
                      transporter, but also as an anion channel. How naturally
                      occurring mutations affect these two transport functions of
                      EAAT2 and how such alterations cause epilepsy is
                      insufficiently understood.MethodsHere we studied the
                      functional consequences of three disease-associated
                      mutations, which predict amino acid exchanges p.Gly82Arg
                      (G82R), p.Leu85Pro (L85P), and p.Pro289Arg (P289R), by
                      heterologous expression in mammalian cells, biochemistry,
                      confocal imaging, and whole-cell patch-clamp recordings of
                      EAAT2 l-glutamate transport and anion current.ResultsG82R
                      and L85P exchange amino acid residues contribute to the
                      formation of the EAAT anion pore. They enlarge the pore
                      diameter sufficiently to permit the passage of l-glutamate
                      and thus function as l-glutamate efflux pathways. The
                      mutation P289R decreases l-glutamate uptake, but increases
                      anion currents despite a lower membrane
                      expression.Significancel-glutamate permeability of the EAAT
                      anion pore is an unexpected functional consequence of
                      naturally occurring single amino acid substitutions.
                      l-glutamate efflux through mutant EAAT2 anion channels will
                      cause glutamate excitotoxicity and neuronal
                      hyperexcitability in affected patients. Antagonists that
                      selectively suppress the EAAT anion channel function could
                      serve as therapeutic agents in the future.},
      cin          = {IBI-1},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-1-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34961934},
      UT           = {WOS:000734862800001},
      doi          = {10.1111/epi.17154},
      url          = {https://juser.fz-juelich.de/record/904700},
}