Phospholipid metabolite 1-palmitoyl-lysophosphatidylcholine enhances human ether-a-go-go-related gene (HERG) K+ channel function

Abstract

Background - Lysophosphatidylcholine (LPC), a naturally occurring phospholipid metabolite, accumulates in the ischemic heart and causes extracellular K+ accumulation and action potential shortening. LPC has been incriminated as a biochemical trigger of lethal cardiac arrhythmias, but the underlying mechanisms remain poorly understood. Methods and Results - We studied the effect of 1-palmitoyl-LPC (Pal-LPC) on currents resulting from human ether-a-go-go-related gene (HERG) expression in human embryonic kidney (HEK) cells using whole-cell patch-clamp techniques. Bath application of Pal-LPC consistently and reversibly increased HERG current (IHERG). The effects of Pal-LPC were apparent as early as 3 minutes after application of the drug, reached maximum within 10 minutes, and were reversible on washout. Pal-LPC increased IHERG at voltages between -20 and +30 mV, with greater effects at stronger depolarization. However, Pal-LPC did not affect the voltage-dependence of IHERG activation. In contrast, Pal-LPC significantly shifted the inactivation curve toward more positive potentials, causing a mean 20.0±2.2 mV shift in half-inactivation voltage relative to control. Conclusions - Our results indicate that apart from being a well-recognized target for drug inhibition, IHERG can also be enhanced by natural substances. An increase in IHERG by Pal-LPC may contribute to K+ loss, abnormal electrophysiology, and arrhythmia occurrence in the ischemic heart.