Illuminating voltage-gated ion channels and their allosteric coupling in slow inactivation processes

In this thesis, voltage-gated ion channels were studied both from a fundamental as a therapeutic viewpoint. In part I, the allosteric coupling between the selectivity filter and the activation gate of the U-type inactivating Kv2.1 and Kv3.1 channels was studied. With the obtained results, a role of the selectivity filter has been proven and more specifically for the second threonine residue of the signature sequence TTVGYG, similar to observations in C-type inactivating Kv channels. Secondly, the Shaker-IR-W434F mutant channel was studied as this channel is often considered as a model for C-type inactivation. However, here it is shown that the W434F mutation stabilizes Shaker in a non-conducting state that is not physiologically relevant. Most surprisingly, in the presence of an activation gate that does not close completely, the W434F-containing selectivity filter dilates during recovery of inactivation to the extend that NMDG conduction could be observed. In the second part of this thesis, the use of voltage gated ion channels as a target for an enhanced photothermal ablation technique was investigated. While several candidate antibodies were validated for binding their extracellular target specifically, a photothermal ablation protocol using gold nanoparticles was optimized for HEK293 and hiPSC-CMs.

Publication year:2022

Keywords:Doctoral thesis

Accessibility:Open