Arachidonic acid metabolites as intracellular modulators of the G protein-gated cardiac K+ channel
Arachidonic acid metabolites as intracellular modulators of the G protein-gated cardiac K+ channel
复制标题
花生四烯酸代谢物作为 G 蛋白门控心脏 K 通道的细胞内调节剂
作者：
Y. Kurachi;Hiroyuki Ito;T. Sugimoto;Takao Shimizu;I. Miki;M. Ui
花生四烯酸从细胞膜释放，以响应各种细胞（包括心肌细胞）的受体依赖性和受体非依赖性刺激1,2。花生四烯酸通过环加氧酶转化为前列腺素，通过 5-脂氧合酶 1 转化为白三烯，这些代谢物具有很强的生物活性，可调节血小板聚集、平滑肌收缩和神经兴奋等细胞功能。然而，其调节背后的分子机制仍然知之甚少。在这里，我们报道花生四烯酸的 5-脂氧合酶代谢物激活百日咳毒素敏感的 G 蛋白门控毒蕈碱 K+ 通道 (IK·ACh)：脂氧合酶抑制剂、去甲二氢愈创木酸和 AA-861 可以阻止花生四烯酸激活 IK·Ach；白三烯A4和C4激活IK·Ach。这种激活发生在经百日咳毒素处理的心房细胞中，并在形成由内而外的斑块时停止，但这些斑块仍然容易受到 GTP 的刺激和 GDP-β-S 的抑制。这些结果表明花生四烯酸代谢物可能以不依赖于受体的方式刺激 G 蛋白。
Arachidonic acid is released from cell membranes in response to receptor-dependent as well as receptor-independent stimulation in various cells, including cardiac myocytes1,2. Arachidonic acid is converted to prostaglandins by cyclooxygenase and to leukotrienes by 5-lipoxygenase1, metabolites which are very biologically active and modulate cellular functions such as platelet aggregation, smooth muscle contraction and neural excitation. The molecular mechanisms underlying their modulations are, however, still badly understood. Here, we report that the 5-lipoxygenase metabolites of arachidonic acid activate the pertussis toxin-sensitive G protein-gated muscarinic K+ channel (IK·ACh): arachidonic acid activation of IK·Ach was prevented by the lipoxygenase inhibitors, nordihydroguaiaretic acid and AA-861; leukotriene A4 and C4 activated IK·Ach. The activation occurred in pertussis toxin-treated atrial cells and ceased when inside-out patches were formed but the patches were still susceptible to stimulation by GTP and to inhibition by GDP-β-S. These results indicate that arachidonic acid metabolites may stimulate the G-protein in a receptor-independent way.