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Title: Do changes in the expression of Gαi2 affect cardiac electrophysiology?
Author: Lane, Jem Daniel Hardee
ISNI:       0000 0004 7962 4237
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2016
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The heterotrimeric G protein subunit, Gαi2, is involved in signal transduction from muscarinic acetylcholine and other receptor systems in cardiomyocytes. Gαi2 expression is elevated in human heart failure, though whether this is beneficial or maladaptive remains unknown. Better understanding could guide therapeutics development. Previous work with Gαi2 knockout mice suggested a pro-arrhythmic phenotype. We hypothesised that increased Gαi2 expression is anti-arrhythmic in the ventricles. To investigate this, an in vivo murine model of myocardial infarction was used to approximate the human pathophysiology, with wild-type (WT) mice compared to those with cardiospecific Gαi2 knockout. Subsequently, an ex vivo model of cardiac tissue slices was used to evaluate normal electrophysiological properties of murine ventricular tissue, alterations with β-adrenoceptor and muscarinic agonists and temperature, and comparison of these properties in WT mice and those with Gαi2 globally deleted. With the myocardial infarction model, there were no significant cardiac phenotypic differences between cardiospecific knockouts and WTs. The cardiac slice model, which utilised a micro-electrode array, showed stable activation and repolarisation properties in WT slices. Comparison of WTs to Gαi2 global knockouts in the presence of carbachol found no significant differences between groups in terms of repolarisation or conduction properties. In WT slices, isoprenaline was associated with a small increase in effective refractory period, but did not alter conduction properties. There was a highly significant negative linear relationship between temperature and both activation, and repolarisation. Murine models were used to investigate the electrophysiological effects of autonomic signalling pathways, and in particular, the protein Gαi2. No observable electrophysiological differences between WT and Gαi2 knockout mice were demonstrated. β-adrenergic agonism produced small changes in repolarisation only. Effects of temperature on activation and refractoriness suggest modulation of sodium and potassium currents, in keeping with published work. These findings contribute to our understanding of autonomic modulation of murine cardiac electrophysiology.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine ; murine cardiac electrophysiology.