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@PHDTHESIS{SudhaBhagavathEswaran:1022314,
      author       = {Sudha Bhagavath Eswaran, Vishal},
      othercontributors = {Carloni, Paolo and Lampert, Angelika and Zimmer-Bensch,
                          Geraldine Marion},
      title        = {{N}aᵥ-igating voltage-gated sodium channels : structure,
                      biophysics and modulation},
      school       = {RWTH Aachen University},
      type         = {Dissertation},
      address      = {Aachen},
      publisher    = {RWTH Aachen University},
      reportid     = {RWTH-2025-09943},
      pages        = {1 Online-Ressource : Illustrationen},
      year         = {2025},
      note         = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
                      University; Dissertation, RWTH Aachen University, 2025},
      abstract     = {Voltage-gated sodium channels (Navs) are important for the
                      transmission of electrical stimuli across neurons, creating
                      the upstroke phase of an action potential. Various
                      channelopathies in these membrane proteins lead to a variety
                      of clinical disease phenotypes, broadly categorizable into
                      either gain or loss of function. Thus, understanding how
                      these channels can be modulated either physiologically or
                      externally by artificially generated compounds will improve
                      our understanding of how these channels function, allowing
                      better strategies for treatment of diseases. In this thesis,
                      I explore the modulatory aspects of Navs using various
                      systems as an example for either physiological (point
                      mutations, membrane composition) or artificial Nav
                      modulation: 1. I utilize a combination of coarse-grained
                      molecular dynamics, whole-cell patch clamp and extracellular
                      protein tagging techniques to show that a loss-of-function
                      mutation successfully trafficking to the membrane can
                      disrupt the geometry of the outer pore and thus block ion
                      conduction. 2. I utilize a modified protocol for
                      coarse-grained molecular dynamics to show the importance of
                      geometry in ensuring proper fast inactivation and how this
                      is disrupted in gain-of-function mutations. 3. I show with
                      in-vitro and in-silico experiments that cholesterol content
                      of the cell membrane is crucial for proper Nav1.7 gating and
                      pharmacological depletion of cholesterol results in
                      gain-of-function of Nav1.7. 4. I predict the local
                      anaesthetic site to be the most probable binding site for
                      the αadrenoreceptor blocker phentolamine in Navs by using
                      computational drug docking strategies. My thesis introduces
                      a novel paradigm on how to understand the structure-function
                      relationships of Navs by combining various in-silico tools
                      with in-vitro techniques. At a molecular level, I establish
                      methods to visualize and analyze structural changes and link
                      them to mechano-functional signatures. I also validate these
                      signatures using in-vitro tools at a cellular level. This in
                      turn allows the investigation of structure-function
                      relationships from multiple angles, augmenting our
                      understanding of Nav interactions with the membrane and
                      modulation by external drugs.},
      cin          = {137810 / 512000-3 ; 921510 / 130000},
      ddc          = {530},
      cid          = {$I:(DE-82)137810_20140620$ / $I:(DE-82)512000-3_20140620$ /
                      $I:(DE-82)130000_20140620$},
      pnm          = {GRK 2416 - GRK 2416: MultiSenses-MultiScales: Neue Ansätze
                      zur Aufklärung neuronaler multisensorischer Integration
                      (368482240)},
      pid          = {G:(GEPRIS)368482240},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.18154/RWTH-2025-09943},
      url          = {https://publications.rwth-aachen.de/record/1022314},
}