Graduate Thesis Or Dissertation
 

Nongenomic action of progesterone inhibits oxytocin signaling through the ovine oxytocin receptor

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  • Experiments were conducted to characterize the nongenomic effects of progesterone (P4) on binding of oxytocin (OT) to the ovine oxytocin receptor (OTR) and signal transduction. The dose-response relationship of P4 to OT binding to the OTR in endometrium was examined. Progesterone interfered with the binding of OT to the OTR in a dose-dependent manner. Endometrium was then recovered from cyclic ewes and divided into explants that were analyzed for total inositol mono- (IP), bis- (IP2), and trisphosphate (IP3) content after exposure to 2.5 ng/ ml P4 and (or) OT. Pre-incubation with P4 for 10 min significantly interfered with OT stimulation of IP3 synthesis. In the next experiment endometrial explants were analyzed for PGF2α response after exposure to OT, arachidonic acid (AA) +OT, P4+OT, and P4 + AA + OT. Treatment of explants with AA increased PGF2α content compared to that of controls. Brief exposure to P4 significantly decreased OT-induced PGF2α secretion from explants previously exposed to medium or AA. The goal of the next study was to determine if P4 would inhibit OT-stimulated phosphoinositide hydrolysis in transfected COS-7 cells with little or no nuclear P4 receptors (nPR). Lack of nPR was confirmed by use of immunocytochemistry and RT-PCR. Pretreatment of COS-7 cells transiently transfected with a plasmid containing the ovine OTR for 10 min with 2.5 ng/ ml P4 significantly interfered with OT-stimulated IP3 production (P4 x OT interaction; P= 0.03). Specificity of steroid inhibition of OT-induced IP3 production was performed. Only P4 was able to significantly inhibit OT-induced IP3 production. A binding assay for R5020, (a synthetic progestin), was performed. There was no measurable specific binding of steroid to both transfected and nontransfected cells. It is concluded that P4 can inhibit OTR-mediated phosphoinositide hydrolysis in COS-7 cells that express little or no nPR protein via some mechanism other than by binding to a membrane progestin receptor.
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