Kurachi Y, Ito H, Sugimoto T, Shimizu T, Miki I, Ui M
2nd Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Nature. 1989 Feb 9;337(6207):555-7. doi: 10.1038/337555a0.
Arachidonic acid is released from cell membranes in response to receptor-dependent as well as receptor-independent stimulation in various cells, including cardiac myocytes. Arachidonic acid is converted to prostaglandins by cyclooxygenase and to leukotrienes by 5-lipoxygenase, 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-beta-S. These results indicate that arachidonic acid metabolites may stimulate the G-protein in a receptor-independent way.
花生四烯酸在包括心肌细胞在内的各种细胞中，响应受体依赖性以及受体非依赖性刺激而从细胞膜释放。花生四烯酸通过环氧化酶转化为前列腺素，通过5-脂氧合酶转化为白三烯，这些代谢产物具有很强的生物活性，并调节细胞功能，如血小板聚集、平滑肌收缩和神经兴奋。然而，其调节的分子机制仍知之甚少。在此，我们报告花生四烯酸的5-脂氧合酶代谢产物激活百日咳毒素敏感的G蛋白门控毒蕈碱钾通道（IK.ACh）：脂氧合酶抑制剂去甲二氢愈创木酸和AA-861可阻止花生四烯酸对IK.ACh的激活；白三烯A4和C4激活IK.ACh。该激活发生在经百日咳毒素处理的心房细胞中，当形成内向外膜片时激活停止，但膜片仍对GTP刺激敏感，并受GDP-β-S抑制。这些结果表明，花生四烯酸代谢产物可能以受体非依赖性方式刺激G蛋白。
