The desensitization of oxytocin receptors in human myometrial cells is accompanied by down-regulation of oxytocin receptor messenger RNA

Abstract

We have recently provided evidence for the desensitization of oxytocin receptors in human myometrial cells. In the present study, we have investigated the possible mechanisms by which oxytocin (OT) might regulate OT receptor density. The steady state level of OT binding in cultured myometrial cells was 220 x 10(3) binding sites/ cell, but this was time-dependently reduced to 27 x 10(3) sites/cell by exposure to OT for up to 20 h. Similarly, OT exposure decreased the binding of OT to cell membranes. In contrast, Western blotting data showed that the total amount of OT receptor protein was not affected by OT treatment for up to 48 h. Flow cytometry experiments demonstrated that OT receptors are not internalized during prolonged exposure of the cells to OT. However, RNase protection assays and Northern analysis showed that OT receptor mRNA was reduced by OT treatment to reach a new low steady state level with a time course similar to that of the disappearance of cell surface OT binding sites. Possible mechanisms involved in mRNA down-regulation include transcriptional suppression and destabilization of mRNA by RNA binding proteins.

Effect of dietary polyunsaturated fatty acids on uterine prostaglandin synthesis in the cow

“…In contrast, CaI would have been able to influence PG generation from both epithelial and stromal cell types, thus contributing to the more sustained response. The loss of responsiveness to OT from 6 to 24 h after challenge is also consistent with previous work showing a time-dependent reduction in both OT-binding sites and mRNA in human myometrial cells exposed to OT for up to 20 h (Phaneuf et al 1997). The reduction in the basal production of PGs from 2 to 24 h after challenge could reflect (i) a reduction in available PLA 2 and/or COX, (ii) a reduction in available precursor or (iii) greater metabolism of PGs during the longer interval between collection times.…”

Molecular regulation of the oxytocin receptor in peripheral organs

“…The amount of OTR mRNA, in contrast, is downregulated. These observations suggest that the OTR molecule is somehow modified such that it loses its oxytocin-binding activity, and that de novo translation of OTR protein would be reduced due to a decrease in the OTR mRNA level (Phaneuf et al 1997). The OTR density as well as the OTR mRNA level was indeed sharply decreased in human myometrium obtained at Caesarean section after prolonged oxytocin-augmented or oxytocin- Figure 1 Complicated regulation of the OTR gene.…”

Sex, parturition and motherhood without oxytocin?

“…In the rat, even very high doses of oxytocin antagonists do not consistently delay the onset of birth in the rat (Chan & Chen 1992), and the delays are relatively short (Antonijevic et al 1995a). Indeed, in the rat, administration of low doses of oxytocin produces a much more effective delay to subsequent birth than administration of high doses of antagonist (Antonijevic et al 1995b), possibly reflecting desensitisation of uterine oxytocin receptors, with decreased receptor density on myometrial cells and reduced oxytocin receptor gene expression (Phaneuf et al 1997), but perhaps also reflecting fatigue of other uterotonic control mechanisms within the uterus. Nonetheless, the onset of parturition in the rat can be advanced by several hours by intravenous infusion of oxytocin, especially if given in pulses (Randolph & Fuchs 1989), and labour is initiated, with variable progression to parturition, at the end of gestation by intermittent electrical stimulation of the neurohypophysis in the rat or rabbit (Lincoln 1971, Boer et al 1975.…”