Barata Hosana, Thompson Michael, Zielinska Weronika, Han Young S, Mantilla Carlos B, Prakash Yedatore S, Feitoza Simone, Sieck Gary, Chini Eduardo N
Signal Transduction Laboratory, Department of Anesthesiology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Endocrinology. 2004 Feb;145(2):881-9. doi: 10.1210/en.2003-0774. Epub 2003 Oct 16.
Human myometrial contraction plays a fundamental role in labor. Dysfunction of uterine contraction is an important cause of labor progression failure. Although the mechanisms controlling uterine contraction are not completely understood, intracellular Ca2+ mobilization plays an important role during uterine contraction. Several mechanisms of intracellular Ca2+ mobilization are present in smooth muscle, but in the human uterus, only 1,4,5-trisphosphate-induced Ca2+ release has been studied extensively. Ryanodine receptor channels are present in myometrium. We determined the role of the cyclic ADP-ribose (cADPR)-signaling pathway in oxytocin-induced intracellular Ca2+ [(Ca2+)i] transients in human myometrial cells. We found that oxytocin-induced Ca2+ transient is dependent on several sources of Ca2+, including extracellular Ca2+ and intracellular Ca2+ stores. In addition, we found that both the 1,4,5-trisphosphate- and the cADPR-induced Ca2+ releasing systems are important for the induction of [Ca2+]i transients by oxytocin in human myometrial cells. Furthermore, we investigated TNFalpha regulation of oxytocin-induced [Ca2+]i transients, CD38 cyclase activity, and CD38 expression in human myometrial cells. We found that oxytocin-induced [Ca2+]i transients were significantly increased by 50 ng/ml TNF. Similarly, CD38 mRNA levels, CD38 expression, and cyclase activity were increased by TNFalpha, thus increasing cADPR levels. We propose that a complex interaction between multiple signaling pathways is important for the development of intracellular Ca2+ transients induced by oxytocin and that TNFalpha may contribute for the myometrium preparation for labor by regulating the cADPR-signaling pathway. The observation that the cADPR-signaling pathway is important for the development of intracellular Ca2+ transients in human myometrial cells raises the possibility that this signaling pathway could serve as a target for the development of new therapeutic strategies for abnormal myometrial contraction observed during pregnancy.
人类子宫肌层收缩在分娩过程中起着基础性作用。子宫收缩功能障碍是分娩进展失败的一个重要原因。尽管控制子宫收缩的机制尚未完全明确，但细胞内钙离子动员在子宫收缩过程中发挥着重要作用。平滑肌中存在多种细胞内钙离子动员机制，但在人类子宫中，仅对1,4,5-三磷酸肌醇诱导的钙离子释放进行了广泛研究。子宫肌层中存在兰尼碱受体通道。我们确定了环二磷酸腺苷核糖（cADPR）信号通路在催产素诱导的人类子宫肌层细胞内钙离子（[Ca2+]i）瞬变中的作用。我们发现，催产素诱导的钙离子瞬变依赖于多种钙离子来源，包括细胞外钙离子和细胞内钙离子储存。此外，我们发现1,4,5-三磷酸肌醇和cADPR诱导的钙离子释放系统对于催产素在人类子宫肌层细胞中诱导[Ca2+]i瞬变均很重要。此外，我们研究了肿瘤坏死因子α（TNFα）对催产素诱导的[Ca2+]i瞬变、CD38环化酶活性以及人类子宫肌层细胞中CD38表达的调节作用。我们发现，50 ng/ml的TNF可使催产素诱导的[Ca2+]i瞬变显著增加50%。同样，TNFα可使CD38 mRNA水平、CD38表达及环化酶活性增加，从而提高cADPR水平。我们提出，多种信号通路之间的复杂相互作用对于催产素诱导的细胞内钙离子瞬变的发生很重要，并且TNFα可能通过调节cADPR信号通路促进子宫肌层为分娩做准备。cADPR信号通路对人类子宫肌层细胞内钙离子瞬变的发生很重要这一观察结果增加了一种可能性，即该信号通路可作为开发针对孕期观察到的子宫肌层异常收缩新治疗策略的靶点。
