Nowicki S, Chen S L, Aizman O, Cheng X J, Li D, Nowicki C, Nairn A, Greengard P, Aperia A
Department of Women and Child Health, Karolinska Institute, Stockholm, Sweden.
J Clin Invest. 1997 Mar 15;99(6):1224-30. doi: 10.1172/JCI119279.
It is well documented that the activity of Na+,K+-ATPase can be inhibited by the arachidonic acid metabolite, 20-hydroxyeicosa-tetraenoic acid (20 HETE). Evidence is presented here that this effect is mediated by protein kinase C (PKC). PKC inhibitors abolished 20 HETE inhibition of rat Na+,K+-ATPase in renal tubular cells. 20 HETE caused translocation of PKC alpha from cytoplasm to membrane in COS cells. It also inhibited Na+,K+-ATPase activity in COS cells transfected with rat wild-type renal Na+,K+-ATPase alpha1 subunit, but not in cells transfected with Na+,K+-ATPase alpha1, where the PKC phosphorylation site, serine 23, had been mutated to alanine. PKC-induced phosphorylation of rat renal Na+,K+-ATPase, as well as of histone was strongly enhanced by 20 HETE at the physiologic calcium concentration of 1.3 microM, but not at the calcium concentration of 200 microM. The results indicate that phospholipase A2-arachidonic acid-20 HETE pathway can exert important biological effects via activation of PKC and that this effect may occur in the absence of a rise in intracellular calcium.
有充分文献记载，花生四烯酸代谢产物20-羟基二十碳四烯酸（20-HETE）可抑制Na⁺,K⁺-ATP酶的活性。本文提供的证据表明，这种效应是由蛋白激酶C（PKC）介导的。PKC抑制剂消除了20-HETE对肾小管细胞中大鼠Na⁺,K⁺-ATP酶的抑制作用。20-HETE导致PKCα在COS细胞中从细胞质转位到细胞膜。它还抑制了用大鼠野生型肾Na⁺,K⁺-ATP酶α1亚基转染的COS细胞中的Na⁺,K⁺-ATP酶活性，但在转染了Na⁺,K⁺-ATP酶α1的细胞中没有抑制作用，在该细胞中PKC磷酸化位点丝氨酸23已突变为丙氨酸。在生理钙浓度1.3微摩尔时，20-HETE强烈增强了PKC诱导的大鼠肾Na⁺,K⁺-ATP酶以及组蛋白的磷酸化，但在钙浓度200微摩尔时没有增强。结果表明，磷脂酶A2-花生四烯酸-20-HETE途径可通过激活PKC发挥重要的生物学效应，并且这种效应可能在细胞内钙不升高的情况下发生。
