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 , 2 , 3 . One of its functions includes maintenance of uterine quiescence by decreasing uterine sensitivity to the uterotonic peptide hormone oxytocin 3 , 4 , 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, non-genomic 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 vitro , 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 5β-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.