CRH对不同信号通路的活化作用可导致分娩前后人类妊娠子宫平滑肌中的差异性钙信号转导

Context: Our previous study has demonstrated that CRH has differential effects on human uterine contractility beforeandafter onset of labor. Intracellular Ca 2+ concentration ([Ca 2+]i) mobilization plays an important role in the control of uterine contraction. Objective: Our objective was to investigate the effects of CRH on [Ca 2+]i homeostasis in laboring and nonlaboring myometrial cells and determine subsequent signaling involved in [Ca 2+]i regulation by CRH. Design: The myometrial tissues were obtained from pregnantwomenwhowere undergoing or not undergoing labor at term. [Ca 2+]i was determined by Ca 2+ imaging system using the fluorescent dye fura-2-acetoxymethyl ester. Western blot analysis, ELISA, and RIA were used to determine the signaling pathways induced by CRH. Results: CRH induced Ca 2+ transient in laboring cells, which was blocked by CRH receptor type 1 (CRHR1) antagonist antalarmin. CRHR1 knockdown impaired this effect of CRH. CRH activated Gi protein, decreased cAMP production, and induced phosphorylated phospholipase C-β3 and inositol- 1,4,5-triphosphate production. Phospholipase C and inositol-1,4,5-triphosphate receptor inhibitors blocked the CRH-induced Ca 2+ transient in laboring cells. CRH did not induce whereas antalarmin induced the Ca 2+ transient in nonlaboring cells. Knockdown of CRHR1 impaired the effect of antalarmin. CRH acted on CRHR1 to activate Gs in nonlaboring cells. Forskolin blocked antalarmin-induced Ca 2+ transient. Conclusions: CRH acts on CRHR1 to activate different signaling pathways before and after onset of labor, thereby resulting in differential calcium signaling in response to CRH. The signaling pathways of CRHR1 might serve as a target for the development of new therapeutic strategies for preterm birth. Copyright © 2012 by The Endocrine Society.

Department of Physiology, Key Laboratory of Molecular Neurobiology, Second Military Medical University, Shanghai 200433, China