The Role of Cyclic-ADP-Ribose-Signaling Pathway in Oxytocin-Induced Ca ²⁺ Transients in Human Myometrium Cells

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⁺),] 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 [Ca ²⁺]; transients by oxytocin in human myometrial cells. Furthermore, we investigated TNFα 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 in creased by 50 ng/ml TNF. Similarly, CD38 mRNA levels, CD38 expression, and cyclase activity were increased by TNFα, 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 TNFα 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 path way could serve as a target for the development of new therapeutic strategies for abnormal myometrial contraction observed during pregnancy.