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Title: Resolving the role of SK channel activation in the mouse heart
Author: Hancock, Jane M.
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
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Atrial Fibrillation (AF) is the most common sustained arrhythmia, affecting approximately 1 % of the population. In its treatment, pharmacological inhibition of repolarising potassium channel currents prolongs the atrial action potential (AP) and refractoriness, but due to a lack of atrial-selectivity the majority of existing drugs can have unwanted proarrhythmic side effects in the ventricles. Small-conductance calcium-activated potassium (SK) channels have been proposed as a promising atrial-selective drug target. However, data in the field are controversial. Although some discrepancies may be due to species differences there are nevertheless direct contradictions. The aim of this study was to confirm the presence of SK channels in the mouse atrium and resolve their functional role in the mouse heart. Three subtypes of SK channels have been cloned (SKI, SK2 and SK3). The presence of SK2 protein in mouse atrial myocytes was confirmed using confocal immunofluorescence microscopy. Whole-cell patch-clamp recordings revealed an outward current in mouse atrial myocytes that was partially inhibited by the SK inhibitors apamin, UCLI684 or NS8593. The effect of NS8593 was unlike that of apamin or UCL1684. Furthermore, NS8593 blocked other heterologously expressed cardiac channels, indicating multichannel block. Apamin inhibited the current in atrial myocytes with an ICso of 118 pM, close to reported values for homomeric SK2 channels. UCLI684 prolonged the AP duration (APD) in isolated mouse atrial myocytes and in the intact atrium. However, UCLI684 prolonged APD significantly more than did apamin, suggesting that there is an apamin-insensitive population of SK channels activated during an action potential. Co-expression of SK2 and SK3 channels in HEK293 cells produced a current with a pharmacology that matched that observed during atrial action potentia Is, suggesting the presence of heteromeric SK2-SK3 channels. Finally, UCLI684 increased beat-to-beat variability in repolarisation raising the possibility that SK inhibition may be pro-arrhythmic.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available