Grazzini E, Guillon G, Mouillac B, Zingg H H
Laboratory of Molecular Endocrinology, Royal Victoria Hospital Research Institute, McGill University, Montreal, Québec, Canada.
Nature. 1998 Apr 2;392(6675):509-12. doi: 10.1038/33176.
The steroid hormone progesterone (P4) is essential for establishing and maintaining pregnancy in mammals. One of its functions includes maintenance of uterine quiescence by decreasing uterine sensitivity to the uterotonic peptide hormone oxytocin. Although it is generally held that steroid hormones such as P4 act at a genomic level by binding to nuclear receptors and modulating the expression of specific target genes, we show here that the effect of P4 on uterine sensitivity to oxytocin involves direct, non-genomic action of P4 on the uterine oxytocin receptor (OTR), a member of the G-protein-coupled receptor family. P4 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 P4 itself but by the P4 metabolite 5beta-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.
类固醇激素孕酮（P4）对于哺乳动物建立和维持妊娠至关重要。其功能之一包括通过降低子宫对宫缩肽激素催产素的敏感性来维持子宫静止。尽管一般认为诸如P4之类的类固醇激素通过与核受体结合并调节特定靶基因的表达而在基因组水平上发挥作用，但我们在此表明，P4对子宫对催产素敏感性的影响涉及P4对子宫催产素受体（OTR，G蛋白偶联受体家族的成员）的直接非基因组作用。P4在体外抑制催产素与含OTR的膜结合，与在CHO细胞中表达的重组大鼠OTR具有高亲和力结合，并抑制催产素诱导的肌醇磷酸生成和钙动员。这些作用具有高度的类固醇和受体特异性，因为密切相关的人OTR的结合和信号功能不受P4本身影响，而是受P4代谢产物5β-二氢孕酮影响。我们的发现为类固醇激素与G蛋白偶联受体之间的直接相互作用提供了首个证据，并确定了肽激素和类固醇激素信号通路之间串扰的新水平。
