Melien O, Winsnes R, Refsnes M, Gladhaug I P, Christoffersen T
Department of Pharmacology, School of Medicine, University of Oslo, Norway.
Eur J Biochem. 1988 Mar 1;172(2):293-7. doi: 10.1111/j.1432-1033.1988.tb13886.x.
Several prostaglandins inhibit the cAMP response to glucagon and beta-adrenergic stimulation in hepatocytes. To probe the mechanism of this inhibition, we have examined in primary hepatocyte cultures how pretreatment with pertussis toxin (islet-activating protein) influences the ability of the cells to respond to hormones and prostaglandins. Pertussis toxin augmented the effects of glucagon, epinephrine and isoproterenol, and also markedly enhanced the cAMP response to prostaglandin E1 (PGE1). Furthermore, whereas PGE1, PGE2, PGI2 and PGF2 alpha attenuated the cAMP responses to glucagon in control cultures, this inhibition was abolished in cells pretreated with pertussis toxin. A more detailed comparison was made of the effects of PGE1 and PGF2 alpha. In cells not treated with pertussis toxin, both these prostaglandins at high concentrations reduced the cAMP response to glucagon and isoproterenol by approximately 50%, but dose-effect curves showed that PGE1 was about 100-fold more potent as an inhibitor than PGF2 alpha. Pertussis toxin abolished the inhibitory effects of PGE1 and PGF2 alpha with almost identical time and dose requirements. The results obtained with PGE1, PGE2, PGI2 and PGF2 alpha suggest that prostaglandins of different series attenuate hormone-activable adenylate cyclase in hepatocytes through a common mechanism, dependent on the inhibitory GTP-binding protein.
几种前列腺素可抑制肝细胞中胰高血糖素和β-肾上腺素能刺激引起的cAMP反应。为了探究这种抑制作用的机制，我们在原代肝细胞培养物中研究了百日咳毒素（胰岛激活蛋白）预处理如何影响细胞对激素和前列腺素的反应能力。百日咳毒素增强了胰高血糖素、肾上腺素和异丙肾上腺素的作用，还显著增强了对前列腺素E1（PGE1）的cAMP反应。此外，在对照培养物中，PGE1、PGE2、前列环素（PGI2）和前列腺素F2α（PGF2α）可减弱对胰高血糖素的cAMP反应，但在用百日咳毒素预处理的细胞中，这种抑制作用消失。对PGE1和PGF2α的作用进行了更详细的比较。在未用百日咳毒素处理的细胞中，这两种前列腺素在高浓度时可使对胰高血糖素和异丙肾上腺素的cAMP反应降低约50%，但剂量效应曲线表明，PGE1作为抑制剂的效力比PGF2α强约100倍。百日咳毒素以几乎相同的时间和剂量要求消除了PGE1和PGF2α的抑制作用。用PGE1、PGE2、PGI2和PGF2α获得的结果表明，不同系列的前列腺素通过一种共同机制减弱肝细胞中激素激活的腺苷酸环化酶，该机制依赖于抑制性GTP结合蛋白。
