Structural determinants of voltage-dependent gating of Kv10.1

von Reham Abdelaziz
Dissertation
Datum der mündl. Prüfung:2021-02-17
Erschienen:2022-01-07
Betreuer:Prof. Dr. Luis A. Pardo
Gutachter:Prof. Dr. Martin Göpfert
Gutachter:Dr. Andreas Neef
Zum Verlinken/Zitieren: http://dx.doi.org/10.53846/goediss-9034

 

 

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Description:PhD Thesis

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Zusammenfassung

Englisch

Voltage-gated ion channels sense voltage through the movement of the voltage sensor in response to change in membrane potential, hence influencing the channel pore. In this project, we seek a deeper understanding of electromechanical coupling in a voltage gated K+ channel: Kv10.1 (EAG1). In most voltage-gated K channels (Kv), the loop between transmembrane segments 4 and 5 (S4-S5 linker) acts as a mechanical lever that couples the movement of the sensor to gate opening. However, recent evidence sets apart the KCNH family (Kv10-12) from this model and proposes a distinct mechanism of gating, where the S4 segment itself, rather than the linker, transduces the movement of the sensor. Nevertheless, the complexity of the gating behaviour of this family of channels is not fully explained by this difference and prompts to the existence of additional mechanisms. In an attempt to identify such alternative mechanisms, we turned our attention to the intracellular ring that characterizes this family and is formed by parts of the large N- and C- terminal intracellular domains. This intracellular ring shows functional and physical interactions with the core of the channel and has been proposed to participate in gating. We generated partial deletions of intracellular domains, generated synthetic cRNA and characterized the properties of the current using two-electrode voltage clamp in Xenopus laevis oocytes. Deletions in both N- and C-terminal domains induce profound alterations in channel kinetics, further reinforcing the notion of their participation in gating. Our data indicates that both the voltage sensor and the ring play a role in electromechanical coupling in KCNH channels.
Keywords: Kv10.1; Gating; Intracellular domains
 
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