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

Signal Transduction Laboratory, Department of Anesthesiology (H.B., M.T., W.Z., S.F., E.N.C.), and Cell Imaging and Physiology Laboratory, Department of Physiology and Biophysics (Y.S.H., C.B.M., Y.S.P., G.S.), Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Eduardo Nunes Chini, Signal Transduction Laboratory, Department of Anesthesiology, Mayo Clinic and Foundation, Rochester, Minnesota 55905. E-mail: chini.eduardo{at}mayo.edu.

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 TNF 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 TNF, 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 TNF 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.

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