A small molecule inhibitor of SUMO prevents the hypoxia-induced decrease in IK1 current.

Abstract

The inward rectifying potassium current (IK1) shapes the initial depolarization and the final repolarization phases of the cardiac action potential and is critical for maintaining the resting membrane potential of ventricular cardiomyocytes. Kir2, the inward rectifying potassium channels are the main contributors to the IK1 current, with Kir2.1 dominating. Disruption of IK1 current activity has been implicated in many cardiac arrhythmia phenotypes. Acute hypoxia during coronary occlusion changes the electrophysiological properties of the myocardium and can precipitate disordered conduction and arrhythmias due to ion channel dysregulation. However, the mechanistic basis for the proarrhythmic effects of acute hypoxia on cardiac tissue has remained unclear, limiting the development of novel therapeutics. Using whole-cell patch-clamp recording we show that acute hypoxia inhibits IK1 in rat ventricular cardiomyocytes, as well as in heterologous expression systems. We provide evidence to show that this inhibition is due to the rapid SUMOylation of Kir2.1 at lysine 49. When SUMO binds to the channel it decreases the efficacy and potency of the membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2) to activate the channel. Finally, we show that a small molecule inhibitor of the SUMO-pathway precludes the hypoxia-mediated decrease in Kir2.1. We confirm that this effect is due to the direct inhibition of Kir2.1 SUMOylation within the cell. These data provide potential insight into investigation of the SUMO pathway as a target for treating the proarrhythmic effects of acute hypoxia.