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@ARTICLE{Rhlmann:886070,
      author       = {Rühlmann, Annika H. and Körner, Jannis and Hausmann, Ralf
                      and Bebrivenski, Nikolay and Neuhof, Christian and
                      Detro‐Dassen, Silvia and Hautvast, Petra and Benasolo,
                      Carène A. and Meents, Jannis and Machtens, Jan-Philipp and
                      Schmalzing, Günther and Lampert, Angelika},
      title        = {{U}ncoupling sodium channel dimers restores the phenotype
                      of a pain‐linked {N}a v 1.7 channel mutation},
      journal      = {British journal of pharmacology},
      volume       = {177},
      number       = {19},
      issn         = {1476-5381},
      address      = {Malden, MA},
      publisher    = {Wiley},
      reportid     = {FZJ-2020-04256},
      pages        = {4481 - 4496},
      year         = {2020},
      abstract     = {Background and PurposeThe voltage‐gated sodium channel
                      Nav1.7 is essential for adequate perception of painful
                      stimuli. Mutations in the encoding gene, SCN9A, cause
                      various pain syndromes in humans. The hNav1.7/A1632E channel
                      mutant causes symptoms of erythromelalgia and paroxysmal
                      extreme pain disorder (PEPD), and its main gating change is
                      a strongly enhanced persistent current. On the basis of
                      recently published 3D structures of voltage‐gated sodium
                      channels, we investigated how the inactivation particle
                      binds to the channel, how this mechanism is altered by the
                      hNav1.7/A1632E mutation, and how dimerization modifies
                      function of the pain‐linked mutation.Experimental
                      ApproachWe applied atomistic molecular simulations to
                      demonstrate the effect of the mutation on channel fast
                      inactivation. Native PAGE was used to demonstrate channel
                      dimerization, and electrophysiological measurements in HEK
                      cells and Xenopus laevis oocytes were used to analyze the
                      links between functional channel dimerization and impairment
                      of fast inactivation by the hNav1.7/A1632E mutation.Key
                      ResultsEnhanced persistent current through hNav1.7/A1632E
                      channels was caused by impaired binding of the inactivation
                      particle, which inhibits proper functioning of the recently
                      proposed allosteric fast inactivation mechanism. hNav1.7
                      channels form dimers and the disease‐associated persistent
                      current through hNav1.7/A1632E channels depends on their
                      functional dimerization status: Expression of the synthetic
                      peptide difopein, a 14‐3‐3 inhibitor known to
                      functionally uncouple dimers, decreased hNav1.7/A1632E
                      channel‐induced persistent currents.Conclusion and
                      ImplicationsFunctional uncoupling of mutant hNav1.7/A1632E
                      channel dimers restored their defective allosteric fast
                      inactivation mechanism. Our findings support the concept of
                      sodium channel dimerization and reveal its potential
                      relevance for human pain syndromes.},
      cin          = {IBI-1 / JARA-HPC},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-1-20200312 / $I:(DE-82)080012_20140620$},
      pnm          = {551 - Functional Macromolecules and Complexes (POF3-551) /
                      Multiscale simulations of voltage-gated sodium channel
                      complexes and clusters $(jics42_20191101)$ / MOLECULAR
                      MODELLING OF BIFUNCTIONAL MEMBRANE TRANSPORT PROTEINS
                      $(jics40_20190501)$},
      pid          = {G:(DE-HGF)POF3-551 / $G:(DE-Juel1)jics42_20191101$ /
                      $G:(DE-Juel1)jics40_20190501$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32663327},
      UT           = {WOS:000563939100001},
      doi          = {10.1111/bph.15196},
      url          = {https://juser.fz-juelich.de/record/886070},
}