Expression, Regulation, and Function of the Calmodulin Accessory Protein PCP4/PEP-19 in Myometrium
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Expression, Regulation, and Function of the Calmodulin Accessory Protein PCP4/PEP-19 in Myometrium
Reproductive Sciences 1-11 ª The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1933719119828072 journals.sagepub.com/home/rsx
Lily He, BS1, Gene T. Lee, MD2,3, Helen Zhou, MD1, Irina A. Buhimschi, MD4,5, Catalin S. Buhimschi, MD4,5, Carl P. Weiner, MD, MB2, and Clifford W. Mason, PhD1,3
Abstract Objective: Calmodulin (CaM) plays a key role in the orchestration of Ca2þ signaling events, and its regulation is considered an important component of cellular homeostasis. The control of uterine smooth muscle function is largely dependent on the regulation of Ca2þ and CaM signaling. The objective of this study was to investigate the expression, function, and regulation of CaM regulatory proteins in myometrium during pregnancy. Study Design: Myometrium was obtained from nonpregnant women and 4 groups of pregnant women at the time their primary cesarean delivery: (i) preterm not in labor, (ii) preterm in labor with clinical and/or histological diagnosis of chorioamnionitis, (3) term not in labor; and (4) term in labor. The effect of perinatal inflammation on pcp4/pep-19 expression was evaluated in a mouse model of Ureaplasma parvum-induced chorioamnionitis. Human myometrial cells stably expressing wild-type and mutant forms of PCP4/PEP-19 were used in the evaluation of agonistinduced intracellular Ca2þ mobilization. Results: Compared to other CaM regulatory proteins, PCP4/PEP-19 transcripts were more abundant in human myometrium. The expression of PCP4/PEP-19 was lowest in myometrium of women with preterm pregnancy and chorioamnionitis. In the mouse uterus, pcp4/pep-19 expression was lower in late compared to mid-gestation and decreased in mice injected intra-amniotic with Ureaplasma parvum. In myometrial smooth muscle cells, tumor necrosis factor alpha and progesterone decreased and PCP4/PEP-19 promoter activity increased. Finally, the overexpression of PCP4/PEP-19 reduced agonist-induced intracellular Ca2þ levels in myometrial cells. Conclusion: The decreased expression of PCP4/PEP-19 in myometrium contributes to a loss of quiescence in response to infection-induced inflammation at preterm pregnancy. Keywords calcium, calmodulin, myometrium, Purkinje cell protein-4
Introduction Throughout pregnancy, the uterus remains relatively quiescent and unresponsive to contractile stimuli. The conversion of the myometrium from a quiescent to an active state during labor is preceded by events that activate smooth muscle cell processes transforming the myometrium to a higher level of excitability. There is also downregulation of mechanisms responsible for uterine relaxation that prepares the uterus for labor.1 Calcium (Ca2þ) is a quintessential second messenger and stimulation of intracellular Ca2þ is the final common pathway leading to smooth muscle contractions.2 Calmodulin (CaM) mediates the effects of Ca2þ and plays a key role in the orchestration of signaling events. Calmodulin interacts w
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