A knock-inDrosophilamodel supports a conserved link between potassium channelopathy and involuntary movement

ABSTRACT Background Genetic and in vitro studies have linked a heterozygous gain-of-function mutation (D434G) in the hSlo1 BK (Big potassium) channel to paroxysmal dyskinesia. However, support for this linkage from in vivo models has been lacking. Objectives We aimed to re-create the equivalent mutation to hSlo1 D434G in the fruit fly, Drosophila , and examine how this mutation altered movement and action potential waveforms. Methods We generated a knock-in Drosophila model of hSlo1 D434G. We used video-tracking and infra-red beam-break systems to test whether locomotion was altered in this model, and patch-clamp electrophysiology to determine how the mutation affected action potential waveforms. Results We identified profound motor dysfunction and sporadic leg twitches, as well as a reduced width and an enhancement of the afterhyperpolarization phase of action potentials, in the model background. Conclusion Our results support a conserved relationship between enhanced BK channel function and disrupted motor control across distantly related species.