The regulation of oxytocin receptor expression in human myometrial monolayer culture.

Clarification of the mechanism of oxytocin (OT)-induced contraction of the uterus seems to be essential for the elucidation of the mechanism of the initiation of labor. Although it has been suggested that estradiol (E) and progesterone (P) are involved in the expression of oxytocin receptors (OTRs), no consensus opinion has been formed on this topic. Thus we recently assessed the effects of E and P on OTR expression using cultures of human uterine cells and we examined the changes in the expressed OTRs following treatment of the cell with exogenous OT. The following results were obtained: 1. The total cellular concentration of OTRs as measured in the myometrial crude membrane fraction (total OTR concentration) showed an increase dependent on the E concentration and on the length of the incubation period in the presence of E. This increase following treatment with E (10(-7) M) was suppressed by simultaneous treatment with P in a concentration-dependent manner; being suppressed by 50% when the concentration of P was 2.7 x 10(-6) M (E/P ratio = 0.037). When 1 nM OT was added to the culture, the total OTR concentration did not change within the first 30 minutes of incubation, but decreased by about 70% twenty-four hours after addition of OT. 2. The concentration of OTRs at the cell surface (surface OTR concentration), as measured in myometrial cells that adhered to the culture plate, did not change with time when the cells were cultured at 4 degrees C in the presence of 1 nM OT. However, when cultured at 37 degrees C, the surface OTR concentration showed decreases dependent on the concentration of OT added and the time after the addition of OT. This change was observed within 60 minutes after the addition of OT to the culture. This decrease in surface OTR concentration was suppressed by concanavalin A (ConA), an inhibition of the internalization of cell surface receptors. These results indicate that in humans also, the expression of myometrial OTRs is regulated by change in the E/P ratio. The present study also revealed that OTRs, once expressed, soon disappear from the cell surface in the presence of exogenous OT (due to internalization of OTRs, i.e., dislocation of OTRs from the cell surface to the inside of the cells), and that prolonged exposure to OT even leads to the disappearance of intracellular OTRs. The present study thus suggests that the expression of human myometrial OTRs is regulated by E and P, and that an agonist-induced desensitization mechanism at the receptor level, similar to that reported for beta-adrenergic receptors, is also operating in this receptor.