https://ogma.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:15716 Wed 11 Apr 2018 17:09:52 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46291 2+-activated K⁺ channel, K_Ca1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of K_Ca1.1 are limited, and KCNMA1 has not been investigated as an AF candidate gene. Methods; The KCNMA1 gene was sequenced in 118 patients with familial AF. The role of K_Ca1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel KCNMA1 variant was functionally characterized.Results: A complex KCNMA1 variant was identified in 1 kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of K_Ca1.1 in normal hearts using immunostaining and immunogold electron microscopy. K_Ca1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the K_Ca1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the K_Ca1.1 ortholog, kcnma1b, in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the Drosophila K_Ca1.1 ortholog, slo, systemically or in adult stages, also slowed the heartbeat and produced fibrillatory cardiac contractions. Electrophysiological characterization of slo-deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human KCNMA1 mutant also showed increased heart period and bursts of action potentials, similar to the K_Ca1.1 loss-of-function models. Conclusions: Our data point to a highly conserved role of K_Ca1.1 in sinus node function in humans, mice, zebrafish, and fly and suggest that K_Ca1.1 loss of function may predispose to AF.]]> Mon 14 Nov 2022 16:44:58 AEDT ]]>