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@ARTICLE{Krner:906898,
      author       = {Körner, Jannis and Albani, Simone and Vishal Sudha
                      Bhagavath Eswaran and Röhl, Anna B and Rossetti, Giulia and
                      Lampert, Angelika},
      title        = {{S}odium channels and local anesthetics – old friends
                      with new perspectives},
      journal      = {Frontiers in pharmacology},
      volume       = {13},
      issn         = {1663-9812},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {FZJ-2022-01753},
      pages        = {837088},
      year         = {2022},
      abstract     = {The long history of local anesthetics (LAs) starts out in
                      the late 19th century when the content of coca plant leaves
                      was discovered to alleviate pain. Soon after, cocaine was
                      established and headed off to an infamous career as a
                      substance causing addiction. Today, LAs and related
                      substances—in modified form—are indispensable in our
                      clinical everyday life for pain relief during and after
                      minor and major surgery, and dental practices. In this
                      review, we elucidate on the interaction of modern LAs with
                      their main target, the voltage-gated sodium channel (Navs),
                      in the light of the recently published channel structures.
                      Knowledge of the 3D interaction sites of the drug with the
                      protein will allow to mechanistically substantiate the
                      comprehensive data available on LA gating modification. In
                      the 1970s it was suggested that LAs can enter the channel
                      pore from the lipid phase, which was quite prospective at
                      that time. Today we know from cryo-electron microscopy
                      structures and mutagenesis experiments, that indeed Navs
                      have side fenestrations facing the membrane, which are
                      likely the entrance for LAs to induce tonic block. In this
                      review, we will focus on the effects of LA binding on fast
                      inactivation and use-dependent inhibition in the light of
                      the proposed new allosteric mechanism of fast inactivation.
                      We will elaborate on subtype and species specificity and
                      provide insights into modelling approaches that will help
                      identify the exact molecular binding orientation, access
                      pathways and pharmacokinetics. With this comprehensive
                      overview, we will provide new perspectives in the use of the
                      drug, both clinically and as a tool for basic ion channel
                      research.},
      cin          = {IAS-5 / INM-9},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {5252 - Brain Dysfunction and Plasticity (POF4-525) / DFG
                      project 291198853 - FOR 2518: Funktionale Dynamik von
                      Ionenkanälen und Transportern - DynIon -},
      pid          = {G:(DE-HGF)POF4-5252 / G:(GEPRIS)291198853},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {35418860},
      UT           = {WOS:000783551000001},
      doi          = {10.3389/fphar.2022.837088},
      url          = {https://juser.fz-juelich.de/record/906898},
}