Role of CD38 in myometrial Ca2+ transients: modulation by progesterone.
Oxytocin-induced Ca(2+) transients play an important role in myometrial contractions. Here, using a knockout model, we found that the enzyme CD38, responsible for the synthesis of the second messenger cyclic ADP-ribose (cADPR), plays an important role in the oxytocin-induced Ca(2+) transients and contraction. We also observed that CD38 is necessary for TNF-alpha-increased agonist-stimulated Ca(2+) transients in human myometrial cells. We provide experimental evidence that the TNF-alpha effect is mediated by increased expression of the enzyme CD38. First, we observed that TNF-alpha increased oxytocin-induced Ca(2+) transients and CD38 expression in human myometrial cells. Moreover, using small interference RNA technology, we observed that TNF-alpha stimulation of agonist-induced Ca(2+) transients was abolished by blocking the expression of CD38. In control experiments, we observed that activation of the component of the TNF-alpha signaling pathway, NF-kappaB, was not affected by the treatments. Finally, we observed that the effects of TNF-alpha on CD38 cyclase and oxytocin-induced Ca(2+) transients are abolished by progesterone. In conclusion, we provide the first experimental evidence that CD38 is important for myometrial Ca(2+) transients and contraction. Moreover, CD38 is necessary for the TNF-alpha-mediated augmentation of agonist-induced Ca(2+) transients in myometrial cells. We propose that the balance between cytokines and placental steroids regulates the expression of CD38 in vivo and cell responsiveness to oxytocin.
Thompson
Michael
M
Dept. of Anesthesiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Barata da Silva
Hosana
H
Zielinska
Weronika
W
White
Thomas A
TA
Bailey
Jeffrey P
JP
Lund
Frances E
FE
Sieck
Gary C
GC
Chini
Eduardo N
EN
D036541:ADP-ribosyl Cyclase / Q000502:physiology*; D051997:ADP-ribosyl Cyclase 1; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D002118:Calcium / Q000819:agonists / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009215:Myometrium / Q000378:metabolism*; D010121:Oxytocin / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015703:Antigens, CD; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D011374:Progesterone; D010121:Oxytocin; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium