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The KCNMA1 Drosophila Ortholog Slowpoke in Drosophila melanogaster Cardiac Function and Human Disease


Aging leads to increases in the incidence and severity of cardiac arrhythmias. The most common of these is atrial fibrillation (AF), which is a major health issue contributing to mortality and affecting some 33.5 million people worldwide [1]. The changes with age that cause increases in AF and how they contribute to the pathophysiology of the disease are questions that are still unanswered. However, researchers long identified a strong heritability component to the disease. A host of different monogenetic candidate gene, linkage analysis and Genome Wide Association Studies (GWAS) followed. These studies led to the discovery of many important cardiac function and disease genes. Yet owing to the inherent complexity of cardiac disease with a wide range of heterogeneic environmental factors, a large portion of the heritable component of disease was still unexplained [2]. One of the first genetic studies looking at AF was linkage analysis study mapping a familial atrial fibrillation locus to chr10q22-q24. However, the study was not able to discern any AF causative genes [3]. Recently, our collaborator, Dr. Diane Fatkin, carried out a screen of affected AF patients and found an association between a case of familial AF and the KCNMA1 gene, which actually spanned the 10q22-q24 locus originally found in the Brugada study. The gene encodes the Big K (BK) channel which was not previously known to have a function in the cardiac action potential. However, examination of this channel in mice has been hampered due to the very rapid kinetics of cardiac repolarization in the mouse versus human heart. Many of the K+ channels underlying the major repolarizing currents in the human do not make key contributions to adult mouse cardiac physiology [4]. In contrast, these channels contribute significantly to Drosophila melanogaster cardiac function [5].

This increased similarity in the channels underlying repolarization between the Drosophila and human cardiac action potential made it an ideal model to study the role of the KCNMA1 homolog slowpoke in the cardiac action potential. In Chapter 3 of this thesis I used Drosophila genetics to temporally and spatially control expression of slowpoke in conjunction with in-house assays to measure cardiac function. The two main assays were video recording and intracellular current clamping of ex-vivo hearts. Both of these showed that slowpoke is important for cardiac function and its absence causes bradyarrhythmias in a cell autonomous fashion. Additionally, I saw that knockdown of slowpoke seemed to downregulate many of the major depolarizing and repolarizing channels in the heart. In Chapter 4 we looked at how the aforementioned human mutation would affect the integrated cardiac system of the fly heart. Finally in Appendix 1 we look at the synergistic phenotypes when different voltage-activated K+ channels, including slowpoke, were knocked down in conjunction. This research points us in the direction to take further steps in dissecting out the repolarizing phase of the Drosophila cardiac action potential and how these mechanisms could translate to human cardiac function and disease.

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