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The prostaglandin (PG) F(2alpha) receptor (FPr) in the corpus luteum is essential for maintaining normal reproductive cyclicity in many species. Activation of this seven-transmembrane spanning receptor at the end of the cycle leads to a decrease in progesterone and the demise of the corpus luteum (luteolysis). Recently, the gene structure of the FPr in three mammalian species has been elucidated; however, promoter regulation of the gene is still poorly understood. The FPr mRNA is extremely low in steroidogenic follicular cells (theca or granulosa) but is expressed at high levels in the corpus luteum, particularly in the large luteal cells. Treatment with PGF(2alpha) decreased FPr mRNA expression in luteal cells in most species that have been studied. Key amino acids have been suggested to be critical for binding of FPr to PGF(2alpha) based on three-dimensional modeling and comparisons with other G-protein-coupled receptors. Moieties of the PGF(2alpha) molecule that are essential for binding or specificity of binding to the FPr have been identified by radioreceptor binding studies. In this article, recent information is reviewed on the structure of the FPr gene, regulation of luteal FPr mRNA, and receptor/ligand interaction requirements for the FPr protein.

Prostaglandins regulate many physiological functions, including reproduction, by binding to specific plasma membrane receptors. In this study we evaluated the regulation of PGF2 alpha (FP) and PGE (EP3 subtype) receptors in ovine corpora lutea. In the first study, tissue distribution of FP and EP3 receptors was evaluated in 13 ovine tissues. FP receptor mRNA was present in 100-fold higher concentration in corpora lutea than in other tissues. Similarly, [3H]PGF2 alpha binding was much greater in luteal plasma membranes than in membranes from other tissues. In contrast, EP3 receptor mRNA was more uniformly distributed, with high concentrations in adrenal medulla, inner myometrium, kidney medulla and heart. The distribution of [3H]PGE1 binding was generally similar to EP3 mRNA, with the exception that ovarian stroma, endometrium and outer myometrium had high [3H]PGE1 binding but low concentrations of EP3 receptor mRNA. The second study evaluated the action of PGF2 alpha on luteal mRNA encoding FP and EP3 receptors. Ewes had PGF2 alpha or saline infused into the ovarian artery and corpora lutea were removed at 0, 1, 4, 12 and 24 h. FP receptor mRNA decreased by 50% at 12 and 24 h after infusion with PGF2 alpha, whereas EP3 mRNA was unchanged. Treatment of large luteal cells with PGF2 alpha, phorbol didecanoate (protein kinase C activator), or ionomycin (calcium ionophore) decreased FP receptor mRNA after 24 h (P < 0.05). Glyceraldehyde 3-phosphate dehydrogenase mRNA was not changed by any treatment. These results show that EP3 receptors are expressed in many tissues and expression is not regulated by PGF2 alpha. In contrast, FP receptors are primarily expressed in corpora lutea and expression is inhibited by PGF2 alpha.

This study provided a pharmacological evaluation of prostaglandin binding to bovine luteal plasma membrane. It was found that [3H]PGF2 alpha' [3H]PGE2' [3H]PGE1 and [3H]PGD2 all bound with high affinity to luteal plasma membrane but had different specificities. Binding of [3H]PGF2 alpha and [3H]PGD2 was inhibited by non-radioactive PGF2 alpha (IC50 values of 21 and 9 nmol l-1, respectively), PGD2 (35 and 21 nmol l-1), and PGE2 (223 and 81 nmol l-1), but not by PGE1 (> 10,000 and 5616 nmol l-1). In contrast, [3H]PGE1 was inhibited by non-radioactive PGE1 (14 nmol l-1) and PGE2 (7 nmol l-1), but minimally by PGD2 (2316 nmol l-1) and PGF2 alpha (595 nmol l-1). Binding of [3H]PGE2 was inhibited by all four prostaglandins, but slopes of the dissociation curves indicated two binding sites. Binding of [3H]PGE1 was inhibited, resulting in low IC50 values, by pharmacological agonists that are specific for EP3 receptor and possibly EP2 receptor. High affinity binding of [3H]PGF2 alpha required a C15 hydroxyl group and a C1 carboxylic acid that are present on all physiological prostaglandins. Specificity of binding for the FP receptor depended on the C9 hydroxyl group and the C5/C6 double bond. Alteration of the C11 position had little effect on affinity for the FP receptor. In conclusion, there is a luteal EP receptor with high affinity for PGE1' PGE2' agonists of EP3 receptors, and some agonists of EP2 receptors. The luteal FP receptor binds PGF2 alpha' PGD2 (high affinity), and PGE2 (moderate affinity) but not PGE1 due to affinity determination by the C9 and C5/C6 moieties, but not the C11 moiety.

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