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

Background-Lysophosphatidylcholine (LPC), a naturally occurring phospholipi d 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 me chanisms remain poorly understood. Methods and Results-We studied the effect of 1-palmitoyl-LPC (Pal-LPC) on c urrents resulting from human ether-a-go-go-related gene (HERG) expression i n human embryonic kidney (HEK) cells using whole-cell patch-clamp technique s. Bath application of Pal-LPC consistently and reversibly increased HERG c urrent (I-HERG). 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 pote ntials, causing a mean 20.0 +/-2.2 mV shift in half-inactivation voltage re lative to control. Conclusions-Our results indicate that apart from being a well-recognized ta rget for drug inhibition, I-HERG can also be enhanced by natural substances . An increase in IHERG by Pal-LPC may contribute to K+ loss, abnormal elect rophysiology, and arrhythmia occurrence in the ischemic heart.