Investigations into the structure, function and pharmacology of TREK K2P potassium channels

Thesis

TREK channels are polymodal potassium channels which act as integrators of diverse chemical and physical stimuli to dynamically control the cellular membrane potential. How the channels sense different stimuli, and how this is transduced to channel gating is not fully understood. Here I report the results of electrophysiological investigations into the structure-function relationship and pharmacology of TREK channels. Firstly, the mechanism of action of plant derived alkylamides at TREK-1 was found to be complex and assay-context dependent. Subsequent studies of TREK-2, guided by recent X-ray crystal structures, provide novel insights into the mechanisms of gating in mechano-, temperature-, arachidonic acid- and pH-modulation. Studying the effect of these different gating stimuli, and the effects of different gating mutations on the potency of state-dependent inhibitors reveals the existence of multiple, distinct open conformations. The results of these studies are consolidated into a structural model for polymodal gating in TREK channels.

Authors: McClenaghan, C

• DOI: 10.5287/ora-4rwe6jk44
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Keywords: ion channels; polymodal gating; patch clamp electrophysiology; pharmacology; TRAAK; norfluoxetine; TREK-2; mechano-sensitivity; K2P; TREK-1