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Title: Functional properties and pharmacological regulation of two-pore domain potassium channels associated with pulmonary disorders
Author: Cunningham, Kevin Peter
ISNI:       0000 0004 7659 5661
Awarding Body: University of Kent
Current Institution: University of Kent
Date of Award: 2018
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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. Carotid bodies are responsible for oxygen sensing within the carotid artery. TASK channels (TASK-1 and TASK-3) are highly expressed in the carotid body and are sensitive to changes in the chemical composition of the blood, stimulating ventilatory responses. This study shows that doxapram, a ventilatory stimulant, is a highly potent inhibitor of both human TASK-1 and TASK-3 channels, despite being a more selective inhibitor of rodent TASK-1 channels. I provide further evidence of the importance of key amino acids, previously identified in rodents, involved in the effect of doxapram on TASK-3. I also show that the M1P1 loop of the channel is important for doxapram inhibition. 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. TREK-1 and TREK-2 channels have been shown to play a role in neuronal pain signalling. The majority of patients undergoing treprostinil therapy, as part of their treatment, experience severe pain at the site of infusion. This study shows that treprostinil rapidly inhibits TREK-1 and TREK-2 channels, suggesting they may play a role in the site pain experienced by patients. I also show that the N-terminus of TREK-1 is not important for treprostinil effect. 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.
Supervisor: Mathie, Alistair ; Veale, Emma Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available