| Summary: | <p>The ability to conduct potassium ions (K<sup>+</sup>) selectively in the abundant presence of other ion species is crucial to the function of K<sup>+</sup> 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<sup>+</sup> channels.</p>
<p>In this project several phenomena related to the permeation, selectivity and gating at the SF of two-pore-domain K<sup>+</sup> channels (K2P channels) were investigated. Firstly, the effect of mutations at the intracellular entrance of the TASK3 (TWIK-related acid sensitive K<sup>+</sup> 3) channel SF were studied. Secondly, the mechanism of pharmacological activation of the TREK2 (TWIK related K<sup>+</sup> 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. </p>
<p>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. </p>
<p>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<sup>+</sup> channel</p>
|
|---|