Inhibition of oxytocin receptor function by direct binding of progesterone

The steroid hormone progesterone (P-4) is essential for establishing and maintaining pregnancy in mammals(1-3). One of its functions includes maintenance of uterine quiescence by decreasing uterine sensitivity to the uterotonic peptide hormone oxytocin(3-5). Although it is generally held that steroid hormones such as P-4 act at a genomic level by binding to nuclear receptors and modulating the expression of specific target genes(6), we show here that the effect of P-4 on uterine sensitivity to oxytocin involves direct, nongenomic action of P-4 on the uterine oxytocin receptor (OTR), a member of the G-protein-coupled receptor family. P-4 inhibits oxytocin binding to OTR-containing membranes in virro, binds with high affinity to recombinant rat OTR expressed in CHO cells, and suppresses oxytocin-induced inositol phosphate production and calcium mobilization. These effects are highly steroid-and receptor-specific, because binding and signalling functions of the closely related human OTR are not affected by P-4 itself but by the P-4 metabolite 5 beta-dihydroprogesterone. Our findings provide the first evidence for a direct Interaction between a steroid hormone and a G-protein-coupled receptor and define a new level of crosstalk between the peptide-and steroid-hormone signalling pathways.