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Am J Physiol Endocrinol Metab 287: E1142-E1148, 2004. First published August 31, 2004; doi:10.1152/ajpendo.00122.2004
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Role of CD38 in myometrial Ca2+ transients: modulation by progesterone

Michael Thompson,1 Hosana Barata da Silva,1 Weronika Zielinska,1 Thomas A. White,2 Jeffrey P. Bailey,2 Frances E. Lund,3 Gary C. Sieck,2 and Eduardo N. Chini1

1Signal Transduction Laboratory, Departments of Anesthesiology and Internal Medicine, and 2Department of Physiology and Mayo Clinic and Foundation, Rochester, Minnesota 55905; and 3Trudeau Institute, Saranac Lake, New York 12983

Submitted 11 March 2004 ; accepted in final form 16 August 2004

Oxytocin-induced Ca2+ 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 Ca2+ transients and contraction. We also observed that CD38 is necessary for TNF-{alpha}-increased agonist-stimulated Ca2+ 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 Ca2+ transients and CD38 expression in human myometrial cells. Moreover, using small interference RNA technology, we observed that TNF-{alpha} stimulation of agonist-induced Ca2+ 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-{kappa}B, was not affected by the treatments. Finally, we observed that the effects of TNF-{alpha} on CD38 cyclase and oxytocin-induced Ca2+ transients are abolished by progesterone. In conclusion, we provide the first experimental evidence that CD38 is important for myometrial Ca2+ transients and contraction. Moreover, CD38 is necessary for the TNF-{alpha}-mediated augmentation of agonist-induced Ca2+ 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.

cyclic adenosine diphosphate-ribose; small interference ribonucleic acid; endoplasmic reticulum; ryanodine channel; tumor necrosis factor-{alpha}


Address for reprint requests and other correspondence: E. N. Chini, Dept. of Anesthesiology, Mayo Clinic and Foundation, Rochester, MN 55905 (E-mail: Chini.eduardo{at}mayo.edu)




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