The Role of Cyclic-ADP-Ribose-Signaling Pathway in Oxytocin-Induced Ca2+ Transients in Human Myometrium Cells

Abstract

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.

Oxytocin-induced elevation of ADP-ribosyl cyclase activity, cyclic ADP-riboseor Ca2+ concentrations is involved in autoregulation of oxytocin secretionin the hypothalamus and posterior pituitary in male mice

“…OT stimulation was dually controlled by IP 3 and cADPR, resembling human myometrium cells (Barata et al, 2004 antagonist delayed the initial peak. In contrast, the cADPR was largely responsible for the sustained Ca 2+ signal for up to 5 min because of blockade by the pretreatment of nerve endings with 8-bromo-cADPR, which was also mimicked by the PKC inhibitor.…”

Modulation of store-operated Ca2+ entry by cyclic-ADP-ribose

“…We have demonstrated that human smooth muscle cells utilize the CD38/cADPR pathway to modulate [Ca 2+ ]i transients during agonist stimulation (18). The components of this pathway are present and functional in myometrial, vascular and airway smooth muscle cells (18)(19)(20)(21)(22)(23)(24).…”

“…Human myometrial cells were isolated using techniques previously described (18). Briefly, the tissue was minced in Hanks' balanced salt solution (HBSS) containing 10 mM glucose and 10 mM HEPES, pH 7.4.…”

Calcium Signaling in Airway Smooth Muscle

“…TNF-a, another important inflammatory cytokine, was previously demonstrated to induce expression of CD38 in airway and myometrial smooth muscles (48,85). The pathophysiologic role of TNF-a is shown by the fact that it is found in high levels in bronchoalveolar lavage fluid and sputum of patients with asthma and chronic obstructive pulmonary disease (86,87).…”