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%0 Thesis
%A Sudha Bhagavath Eswaran, Vishal
%T Naᵥ-igating voltage-gated sodium channels : structure, biophysics and modulation
%I RWTH Aachen University
%V Dissertation
%C Aachen
%M RWTH-2025-09943
%P 1 Online-Ressource : Illustrationen
%D 2025
%Z Veröffentlicht auf dem Publikationsserver der RWTH Aachen University
%Z Dissertation, RWTH Aachen University, 2025
%X 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.
%F PUB:(DE-HGF)11
%9 Dissertation / PhD Thesis
%R 10.18154/RWTH-2025-09943
%U https://publications.rwth-aachen.de/record/1022314