Résumé
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.