Direct activation of an inwardly rectifying potassium channel by arachidonic acid.
Direct activation of an inwardly rectifying potassium channel by arachidonic acid.
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DOI：
10.1124/mol.59.5.1061
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发表时间：
2001-05
影响因子：
3.6
通讯作者：
Yi Liu;Dong Liu;Louise Heath;D. M. Meyers;D. Krafte;P. Wagoner;Christopher P. Silvia;Weifeng Yu-Weifeng
中科院分区：
文献类型：
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作者：
Yi Liu;Dong Liu;Louise Heath;D. M. Meyers;D. Krafte;P. Wagoner;Christopher P. Silvia;Weifeng Yu-Weifeng
花生四烯酸（AA）是膜磷脂的重要组成部分，可通过激活细胞磷脂酶释放。AA通过多种机制调节多种离子通道，包括AA本身的直接作用和AA代谢产物的间接作用。在这里，我们报告了AA对克隆的人内向整流K（+）通道Kir2.3的兴奋作用，Kir2.3在大脑和心脏中高度表达，在调节细胞兴奋性方面至关重要。在全细胞和切除的宏斑记录中，AA有效且可逆地增加Kir2.3电流幅度（对AA的最大全细胞反应为对照的258 +/- 21%，在-97 mV下EC（50）值为447 nM）。这种效果显然是由AA在细胞外位点的作用引起的，并且不能通过蛋白激酶C、自由氧自由基或AA代谢途径的抑制剂来防止。不是代谢底物的脂肪酸也增强Kir2.3电流。AA对流经Kir2.1、Kir2.2和Kir2.4通道的电流无影响。Kir2.1/2.3嵌合体的实验表明，虽然AA可以结合Kir2.1和Kir2.3，跨膜和/或细胞内域的Kir2.3通道增强是必不可少的。这些结果证明了AA调节Kir2.3的直接机制。
Arachidonic acid (AA) is an important constituent of membrane phospholipids and can be liberated by activation of cellular phospholipases. AA modulates a variety of ion channels via diverse mechanisms, including both direct effects by AA itself and indirect actions through AA metabolites. Here, we report excitatory effects of AA on a cloned human inwardly rectifying K(+) channel, Kir2.3, which is highly expressed in the brain and heart and is critical in regulating cell excitability. AA potently and reversibly increased Kir2.3 current amplitudes in whole-cell and excised macro-patch recordings (maximal whole-cell response to AA was 258 +/- 21% of control, with an EC(50) value of 447 nM at -97 mV). This effect was apparently caused by an action of AA at an extracellular site and was not prevented by inhibitors of protein kinase C, free oxygen radicals, or AA metabolic pathways. Fatty acids that are not substrates for metabolism also potentiated Kir2.3 current. AA had no effect on the currents flowing through Kir2.1, Kir2.2, or Kir2.4 channels. Experiments with Kir2.1/2.3 chimeras suggested that, although AA may bind to both Kir2.1 and Kir2.3, the transmembrane and/or intracellular domains of Kir2.3 were essential for channel potentiation. These results argue for a direct mechanism of AA modulation of Kir2.3.