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Asymmetric Interplay Between K⁺ and Blocker and Atomistic Parameters From Physiological Experiments Quantify K⁺ Channel Blocker Release

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  • معلومة اضافية
    • Publisher Information:
      Frontiers Media S.A. 2023-12-05
    • نبذة مختصرة :
      Modulating the activity of ion channels by blockers yields information on both the mode of drug action and on the biophysics of ion transport. Here we investigate the interplay between ions in the selectivity filter (SF) of K⁺ channels and the release kinetics of the blocker tetrapropylammonium in the model channel KcvNTS. A quantitative expression calculates blocker release rate constants directly from voltage-dependent ion occupation probabilities in the SF. The latter are obtained by a kinetic model of single-channel currents recorded in the absence of the blocker. The resulting model contains only two adjustable parameters of ion-blocker interaction and holds for both symmetric and asymmetric ionic conditions. This data-derived model is corroborated by 3D reference interaction site model (3D RISM) calculations on several model systems, which show that the K⁺ occupation probability is unaffected by the blocker, a direct consequence of the strength of the ion-carbonyl attraction in the SF, independent of the specific protein background. Hence, KcvNTS channel blocker release kinetics can be reduced to a small number of system-specific parameters. The pore-independent asymmetric interplay between K⁺ and blocker ions potentially allows for generalizing these results to similar potassium channels.
    • الموضوع:
      Article; NonPeerReviewed; info:eu-repo/semantics/article
    • Availability:
      Open access content. Open access content
      CC BY 4.0 International - Creative Commons, Attribution
      CC BY 4.0 International - Creative Commons, Attribution
      CC BY 4.0 International - Creative Commons, Attribution
      info:eu-repo/semantics/openAccess
    • Note:
      text
      text
      spreadsheet
      English
    • Other Numbers:
      DETUD oai:tuprints.ulb.tu-darmstadt.de:19966
      Gabriel, Tobias S. ; Hansen, Ulf-Peter ; Urban, Martin ; Drexler, Nils ; Winterstein, Tobias ; Rauh, Oliver ; Thiel, Gerhard ; Kast, Stefan M. ; Schroeder, Indra (2023)Asymmetric Interplay Between K⁺ and Blocker and Atomistic Parameters From Physiological Experiments Quantify K⁺ Channel Blocker Release. In: Frontiers in Physiology, 2021, 12 doi: 10.26083/tuprints-00019966 Article, Secondary publication, Publisher's Version
      1418823725
    • Contributing Source:
      TECHNISCHE UNIV DARMSTADT
      From OAIster®, provided by the OCLC Cooperative.
    • الرقم المعرف:
      edsoai.on1418823725
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