title: 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.
authors.affiliation: Signal Transduction Laboratory, Department of Anesthesiology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
authors.forename: Hosana
authors.initials: H
authors.lastname: Barata
authors.forename: Michael
authors.initials: M
authors.lastname: Thompson
authors.forename: Weronika
authors.initials: W
authors.lastname: Zielinska
authors.forename: Young S
authors.initials: YS
authors.lastname: Han
authors.forename: Carlos B
authors.initials: CB
authors.lastname: Mantilla
authors.forename: Yedatore S
authors.initials: YS
authors.lastname: Prakash
authors.forename: Simone
authors.initials: S
authors.lastname: Feitoza
authors.forename: Gary
authors.initials: G
authors.lastname: Sieck
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Chini
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000032:analysis / Q000235:genetics; D051997:ADP-ribosyl Cyclase 1; D000328:Adult; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics; D002118:Calcium / Q000378:metabolism*; D036563:Cyclic ADP-Ribose / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D008562:Membrane Glycoproteins; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009215:Myometrium / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D010121:Oxytocin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D019837:Ryanodine Receptor Calcium Release Channel / Q000032:analysis; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014590:Uterine Contraction
chemical_list: D015703:Antigens, CD; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D014409:Tumor Necrosis Factor-alpha; D036563:Cyclic ADP-Ribose; D010121:Oxytocin; D015544:Inositol 1,4,5-Trisphosphate; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium