Control of cardiac rhythm by ORK1, a Drosophila two-pore domain potassium channel

Abstract

Unravelling the mechanisms controlling cardiac automatism is critical to our comprehension of heart development and cardiac physiopathology. Despite the extensive characterization of the ionic currents at work in cardiac pacemakers, the precise mechanisms initiating spontaneous rhythmic activity and, particularly, those responsible for the specific control of the pacemaker frequency are still matters of debate and have not been entirely elucidated. By using Drosophila as a model animal to analyze automatic cardiac activity, we have investigated the function of a K+ channel, ORK1 (outwardly rectifying K+ channel-1) in cardiac automatic activity. ORK1 is a two-pore domain K+ (K2P) channel, which belongs to a diverse and highly regulated superfamily of potassium-selective leak channels thought to provide baseline regulation of membrane excitability. Cardiac-specific inactivation of Ork1 led to an increase in heart rhythm. By contrast, when overexpressed, ORK1 completely prevented heart beating. In addition, by recording action potentials, we showed that the level of Ork1 activity sets the cardiac rhythm by controlling the duration of the slow diastolic depolarization phase. Our observations identify a new mechanism for cardiac rhythm control and provide the first demonstration that K2P channels regulate the automatic cardiac activity.