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 ϩ 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 (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 I HERG at voltages between Ϫ20 and ϩ30 mV, with greater effects at stronger depolarization. However, Pal-LPC did not affect the voltage-dependence of I HERG activation. In contrast, Pal-LPC significantly shifted the inactivation curve toward more positive potentials, causing a mean 20.0Ϯ2.2 mV shift in half-inactivation voltage relative to control. Conclusions-Our results indicate that apart from being a well-recognized target for drug inhibition, I HERG can also be enhanced by natural substances. An increase in I HERG by Pal-LPC may contribute to K ϩ loss, abnormal electrophysiology, and arrhythmia occurrence in the ischemic heart. (Circulation. 2001;104:2645-2648.)

Downregulation of the HERG (KCNH2) K+ channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation

“…The addition of I HERG to this list appears to be expected as a related inwardly rectifying potassium current of lactotrophs and neuroblastoma cells is also inhibited by ceramide (Wu et al, 2001). The inhibitory mechanism of ceramide on the I K(IR) of GH 3 lactotrophs was unresolved and disparities exist though from our present findings, or those of Wang et al (Wang et al, 2001). Specifically a robust inhibition within one minute of ceramide application (~70% with 10 M C 2 ) was shown and a +10 mV shift of the activation curve (Wu et al, 2001).…”

“…These differences probably emanate from the cellular systems used, where such contributing factors could include heterogeneous ERG current properties owing to the presence of non-cardiac ERG family member subunits (Schäfer et al, 1999;Wimmers et al, 2002), and diversity of signalling (Barros et al, 1998;Schäfer et al, 1999). However, using HEK293 cells stably expressing HERG, as here, Wang et al (Wang et al, 2001) observed that ceramide had no significant effects on I HERG . The reason for this discrepancy is presently not known, but may arise from the time-dependent nature of the effect evident here, and from differences in the concentration of ceramide used.…”

Impairment of HERG K+ Channel Function by Tumor Necrosis Factor-α

“…Whole-cell Patch Clamp Recording-Patch clamp techniques have been described in detail elsewhere (13)(14)(15)(16). Experiments were conducted at 36 Ϯ 1°C.…”

Impairment of Human Ether-à-Go-Go-related Gene (HERG) K+ Channel Function by Hypoglycemia and Hyperglycemia

“…Whole-cell Patch Clamp Recording-Patch clamp techniques have been described in detail elsewhere (15)(16). Currents were recorded with whole-cell voltage clamp with an Axopatch-200B amplifier (Axon Instruments).…”