Potential mechanisms for the enhancement of HERG K+ channel function by phospholipid metabolites
Potential mechanisms for the enhancement of HERG K+ channel function by phospholipid metabolites
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DOI：
10.1038/sj.bjp.0705646
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发表时间：
2004-02-01
影响因子：
7.3
通讯作者：
Wang, ZG
中科院分区：
文献类型：
--
作者：
Wang, JX;Zhang, YQ;Wang, ZG
1 磷脂代谢物溶血磷脂会导致细胞外 K+ 积累和动作电位缩短，从而增加心肌缺血期间发生心律失常的风险。在这里，我们研究了几种具有不同长度烃链和带电头基的溶血磷脂对 HEK293 细胞中表达的 HERG K+ 电流 I-HERG) 的影响，以及使用全细胞膜片钳技术的潜在机制。2 仅具有 16 种碳氢化合物的脂质，例如 1-棕榈酰-溶血磷脂酰胆碱 (LPC-16) 和 1-棕榈酰-溶血磷脂酰甘油(LPG-16) 被发现可显着增强 I-HERG 和 HERG 激活的负移，尽管 LPC-16 和具有不同电荷头基的 LPG-16 之间效果的电压依赖性不同。含有 18 种碳氢化合物的脂质适度增加了 I-HERG。具有 6 或 24 个碳氢化合物的脂质没有影响或轻微降低 I-HERG。3 蛋白激酶 C 的抑制或激活不会改变 LPC-16 和 LPG-16 的影响。 4,5-二磷酸磷脂酰肌醇参与 LPC-16/LPG-16 增强 I-HERG 的作用也被排除。4 维生素 E 增强 LPC-16/LPG-16 的作用，而黄嘌呤/黄嘌呤氧化酶降低 I-HERG：表明 LPC-16/LPG-16 对 I-HERG 产生双重作用：直接增强 I-HERG 和通过产生超氧化物间接抑制5 我们得出结论，溶血磷脂对 HERG 功能的增强是具有 16-烃链结构的脂质所特有的，并且电压依赖性模式由极性头基决定。 I-HERG 的增加最好通过脂质分子和 HERG 蛋白之间的直接相互作用来描述，这与缺乏通过膜不稳定或细胞内信号传导途径调节的影响是一致的。
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.