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@ARTICLE{Albani:1030737,
      author       = {Albani, Simone and Eswaran, Vishal Sudha Bhagavath and
                      Piergentili, Alessia and de Souza, Paulo Cesar Telles and
                      Lampert, Angelika and Rossetti, Giulia},
      title        = {{D}epletion of membrane cholesterol modifies structure,
                      dynamic and activation of {N}av1.7},
      journal      = {International journal of biological macromolecules},
      volume       = {278},
      issn         = {0141-8130},
      address      = {New York, NY [u.a.]},
      publisher    = {Elsevier},
      reportid     = {FZJ-2024-05444},
      pages        = {134219 -},
      year         = {2024},
      abstract     = {Cholesterol is a major component of plasma membranes and
                      plays a significant role in actively regulating the
                      functioning of several membrane proteins in humans. In this
                      study, we focus on the role of cholesterol depletion on the
                      voltage-gated sodium channel Nav1.7, which is primarily
                      expressed in the peripheral sensory neurons and linked to
                      various chronic inherited pain syndromes. Coarse-grained
                      molecular dynamics simulations revealed key dynamic changes
                      of Nav1.7 upon membrane cholesterol depletion: A loss of
                      rigidity in the structural motifs linked to activation and
                      fast-inactivation is observed, suggesting an easier
                      transition of the channel between different gating states.
                      In-vitro whole-cell patch clamp experiments on HEK293t cells
                      expressing Nav1.7 validated these predictions at the
                      functional level: Hyperpolarizing shifts in the
                      voltage-dependence of activation and fast-inactivation were
                      observed along with an acceleration of the time to peak and
                      onset kinetics of fast inactivation. These results underline
                      the critical role of membrane composition, and of
                      cholesterol in particular, in influencing Nav1.7 gating
                      characteristics. Furthermore, our results also point to
                      cholesterol-driven changes of the geometry of drug-binding
                      regions, hinting to a key role of the membrane environment
                      in the regulation of drug effects.},
      cin          = {INM-9},
      ddc          = {570},
      cid          = {I:(DE-Juel1)INM-9-20140121},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {39097041},
      UT           = {WOS:001295816700001},
      doi          = {10.1016/j.ijbiomac.2024.134219},
      url          = {https://juser.fz-juelich.de/record/1030737},
}