Asbóth G, Phaneuf S, López Bernal A L
1st Institute of Biochemistry, Semmelweis University of Medicine, Budapest, Hungary.
Acta Physiol Hung. 1997;85(1):39-50.
Prostaglandins (PGs) exert their effects via binding to specific cell surface receptors and influencing second messenger systems through G-proteins. PGE2 may interact with at least four receptor subtypes (EP1, EP2, EP3, EP4), each showing different pharmacological profiles. The second messengers calcium, inositol phosphates (InsPs) and cyclic nucleotides play decisive roles in uterine contractility. The question in this investigation was, which EP receptors, G-proteins and second messenger systems transmit PGE2 induced signals in human myometrium. We have measured changes in InsPs and cAMP formation and also in intracellular calcium concentration ([Ca2+]i) induced by PGE2 and receptor subtype selective analogues in cultured human myometrial cells. PGE2 increased cAMP level and this effect was shared by the EP2 receptor subtype selective agonist Butaprost and by Misoprostol (EP3 > EP2 > EP1). Sulprostone (EP3 > EP1) did not stimulate adenylyl cyclase activity per se, but inhibited forskolin-stimulated adenylyl cyclase in a pertussis toxin (PT) sensitive way. PGE2, GR63799X (EP3 selective), Sulprostone and Misoprostol activated phospholipase-C (PLC), this effect was resistant to PT treatment. PGE2 also elevated [Ca2+]i from the resting level of 60-90 nM up to 350 nM. Low concentrations (1-300 nM) of PGE2 increased [Ca2+]i without PLC activation. The selective EP1 inhibitor AH6809, Nifedipine, Verapamil and PT treatment inhibited this effect of PGE2. In cultured human myometrial cells PGE2 interacts with EP1 receptors, which elevate [Ca2+]i independently from PLC, but involving a Gi protein and plasmamembrane calcium channels; EP2 receptors which stimulate adenylyl cyclase; EP3A receptors, which inhibit adenylyl cyclase activity through Gi activation and EP3D receptors which activate PLC through a PT-insensitive pathway and also elevate [Ca2+]i.
前列腺素（PGs）通过与特定细胞表面受体结合并通过G蛋白影响第二信使系统来发挥其作用。前列腺素E2（PGE2）可能与至少四种受体亚型（EP1、EP2、EP3、EP4）相互作用，每种亚型都表现出不同的药理学特征。第二信使钙、肌醇磷酸（InsPs）和环核苷酸在子宫收缩中起决定性作用。本研究的问题是，哪些EP受体、G蛋白和第二信使系统在人子宫肌层中传递PGE2诱导的信号。我们测量了培养的人子宫肌层细胞中InsPs和环磷酸腺苷（cAMP）形成的变化以及PGE2和受体亚型选择性类似物诱导的细胞内钙浓度（[Ca2+]i）的变化。PGE2增加了cAMP水平，这种作用由EP2受体亚型选择性激动剂布他前列素和米索前列醇（EP3 > EP2 > EP1）共同具有。舒前列素（EP3 > EP1）本身不刺激腺苷酸环化酶活性，但以百日咳毒素（PT）敏感的方式抑制福斯高林刺激的腺苷酸环化酶活性。PGE2、GR63799X（EP3选择性）、舒前列素和米索前列醇激活磷脂酶C（PLC），这种作用对PT处理具有抗性。PGE2还将[Ca2+]i从60 - 90 nM的静息水平提高到350 nM。低浓度（1 - 300 nM）的PGE2在不激活PLC的情况下增加[Ca2+]i。选择性EP1抑制剂AH6809、硝苯地平、维拉帕米和PT处理抑制了PGE2的这种作用。在培养的人子宫肌层细胞中，PGE2与EP1受体相互作用，后者独立于PLC升高[Ca2+]i，但涉及Gi蛋白和质膜钙通道；EP2受体刺激腺苷酸环化酶；EP3A受体通过激活Gi抑制腺苷酸环化酶活性，EP3D受体通过PT不敏感途径激活PLC并升高[Ca2+]i。
