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Title: Investigation of K2P channel permeation and gating
Author: Conrad, Linus Johann
ISNI:       0000 0004 8507 901X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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The ability to conduct potassium ions (K+) selectively in the abundant presence of other ion species is crucial to the function of K+ channels. While the mechanism of ion selectivity has been an in- tensely studied and debated topic, the protein structure responsible for ion-selectivity has long been identified as the so called selectivity filter (SF). The SF also doubles as the principal regulatory element (gate) in many K+ channels. In this project several phenomena related to the permeation, selectivity and gating at the SF of two-pore-domain K+ channels (K2P channels) were investigated. Firstly, the effect of mutations at the intracellular entrance of the TASK3 (TWIK-related acid sensitive K+ 3) channel SF were studied. Secondly, the mechanism of pharmacological activation of the TREK2 (TWIK related K+ channel 2) SF gate was probed on a single molecule level. Channel activation was found to be conferred by a change to the electrostatic milieu at the SF entrance. Following from this electrostatic mechanism the dependence of gating on salt concentration (ionic strength) was probed. Here an unusual property emerged: TREK channels close in the presence of high ionic strength. Finally, evidence was found that TREK2 may change its ion- selectivity in the context of voltage-dependent gating. This result suggests that TREK2 may have a stimulating effect on cellular exciteability, which is a novel and atypical property for a K+ channel.
Supervisor: Tucker, Stephen ; Carpenter, Liz Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available