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


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 -20 and +30 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 20.0+/-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, I(HERG) can also be enhanced by natural substances. An increase in I(HERG) by Pal-LPC may contribute to K(+) loss, abnormal electrophysiology, and arrhythmia occurrence in the ischemic heart.
Wang
J
J
Research Center, Montreal Heart Institute, Montreal, Canada.
Wang
H
H
Han
H
H
Zhang
Y
Y
Yang
B
B
Nattel
S
S
Wang
Z
Z
D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism; D027682:Cation Transport Proteins; D002460:Cell Line; D002518:Ceramides / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D015870:Gene Expression; D006801:Humans; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000378:metabolism / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010743:Phospholipids / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D027682:Cation Transport Proteins; D002518:Ceramides; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D008244:Lysophosphatidylcholines; D010743:Phospholipids; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C006065:We 201