Potential mechanisms for the enhancement of HERG K+ channel function by phospholipid metabolites.
1. Phospholipid metabolites lysophospholipids cause extracellular K(+) accumulation and action potential shortening with increased risk of arrhythmias during myocardial ischemia. Here we studied effects of several lysophospholipids with different lengths of hydrocarbon chains and charged headgroups on HERG K(+) currents (I(HERG)) expressed in HEK293 cells and the potential mechanisms using whole-cell patch-clamp techniques. 2. Only the lipids with 16 hydrocarbons such as 1-palmitoyl-lysophosphatidylcholine (LPC-16) and 1-palmitoyl-lysophosphatidylglycerol (LPG-16) were found to produce significant enhancement of I(HERG) and negative shifts of HERG activation, although the voltage dependence of the effects was different between LPC-16 and LPG-16 which have differently charged headgroups. The lipid with 18 hydrocarbons modestly increased I(HERG). The lipids with 6 or 24 hydrocarbons had no effect or slightly decreased I(HERG). 3. Inhibition or activation of protein kinase C did not alter the effects of LPC-16 and LPG-16. Participation of phosphatidylinositol-4,5-bisphosphate in I(HERG) enhancement by LPC-16/LPG-16 was also excluded. 4. Vitamin E augmented the effects of LPC-16/LPG-16 whereas xanthine/xanthine oxidase reduced I(HERG): indicating that LPC-16/LPG-16 produced dual effects on I(HERG): direct enhancement of I(HERG) and indirect suppression via production of superoxide anion. 5. We conclude that enhancement of HERG function by lysophospholipids is specific to the lipids with 16-hydrocarbon chain structure and the pattern of voltage dependence is determined by the polar headgroups. The increase in I(HERG) is best described by direct interactions between lipid molecules and HERG proteins, which is consistent with lack of effects via membrane destabilization or modulation by intracellular signaling pathways.
Wang
Jingxiong
J
Research Center, Montreal Heart Institute, and Department of Medicine, University of Montreal, Canada.
Zhang
Yiqiang
Y
Wang
Huizhen
H
Han
Hong
H
Nattel
Stanley
S
Yang
Baofeng
B
Wang
Zhiguo
Z
D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists*; D024642:Potassium Channels, Voltage-Gated; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006838:Hydrocarbons; C000606913:KCNH2 protein, human; D008244:Lysophosphatidylcholines; D019269:Phosphatidylinositol 4,5-Diphosphate; D010743:Phospholipids; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D014810:Vitamin E; C006065:We 201; D011493:Protein Kinase C