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Functional Properties and Pharmacological Regulation of Two-Pore Domain Potassium Channels Associated with Pulmonary Disorders

Cunningham, Kevin Peter (2018) Functional Properties and Pharmacological Regulation of Two-Pore Domain Potassium Channels Associated with Pulmonary Disorders. Doctor of Philosophy (PhD) thesis, University of Kent,.

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Abstract

Potassium (K+) channels have been found to regulate the background 'leak' current maintaining resting membrane potential and therefore controlling the excitability of mammalian cells. The two-pore domain K+ channel (K2P) family has been suggested to underlie the K+ channels responsible for this leak current and can be regulated by a variety of stimuli. This study investigated multiple K2P channels and their role within pulmonary disorders using a combination of electrophysiological, imaging and biochemical approaches.

TASK-1 channels have been implicated in pulmonary arterial hypertension (PAH). I characterised homozygous mutations of TASK-1, G106R and L214R, found in patients diagnosed with an aggressive form of PAH. I show that whilst the mutated TASK-1 channels are expressed and trafficked to the membrane, they appear to be non-functional. Riociguat and sildenafil, used in the treatment of PAH, enhanced current through WT TASK-1 channels but were unable to restore function through the mutated TASK-1 channels.

K2P channels play a key role within the pulmonary system and their ability to be regulated by a variety of stimuli makes them a key therapeutic target when treating pulmonary disorders.

Item Type: Thesis (Doctor of Philosophy (PhD))
Thesis advisor: Mathie, Alistair
Thesis advisor: Veale, Emma
Uncontrolled keywords: Pulmonary Arterial Hypertension, Two-Pore Domain Potassium Channels, Ion Channels
Divisions: Faculties > Sciences > Medway School of Pharmacy
SWORD Depositor: System Moodle
Depositing User: System Moodle
Date Deposited: 06 Mar 2019 10:10 UTC
Last Modified: 01 Oct 2019 23:00 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/72858 (The current URI for this page, for reference purposes)
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