Prostaglandin F2 alpha is a metabolite of arachidonic acid that triggers regression of the corpus luteum and uterine contraction. Its actions are mediated by a cell-surface receptor (FP); the cDNAs of FP receptor of several species were cloned (Sakamoto et al., 1995; Lake et al., 1994; Graves et al., 1995). These receptors belong to the seven tansmembrane domain G-coupled receptor family.
General function
Receptor
Comment
The first successful cloning of functional receptor cDNA for PGF2 alpha was carried out by Sakamoto et al. (1994). This clone encodes a protein of 362 amino acid residues (M(r) = 40,983) with seven potential transmembrane domains and represents significant overall sequence homology to human TXA2 receptor protein (34% in amino acid). Injection of the mRNA synthesized in vitro from the cloned cDNA into a Xenopus oocyte elicited electrophysiological response to PGF2 alpha. Ligand binding displacement in membranes of mammalian COS-7 cells transfected with the cDNA indicated the rank order of affinity of the receptor to PGs: PGF2 alpha > PGD2 > PGE2 > STA2, a TXA2
agonist. PGF2 alpha activated inositol phosphate formation in COS-7 cells transfected with receptor cDNA. Northern blot analysis and in situ hybridization indicated, that the PGF2 alpha receptor mRNA is expressed and accumulated in the corpus luteum.
Cellular localization
Plasma membrane
Comment
Ovarian function
Ovulation, Steroid metabolism, Luteolysis
Comment
Auto-amplification system for prostaglandin F2a in bovine corpus luteum. Kumagai A 2014 et al.
The bovine corpus luteum (CL) is hypothesized to utilize a local auto-amplification system for prostaglandin (PG) F2a production. The objective of the present study was to determine if such a PGF2a auto-amplification system exists in the bovine CL, and if so, which factors regulate it. PGF2a significantly stimulated intra-luteal PGF2a production in all luteal phases, but did not affect PGE2 production. The stimulatory effect of exogenous PGF2a on CL PGF2a production was lower at the early luteal phase. Indomethacin, an inhibitor of prostaglandin-endoperoxide synthase (PTGS), significantly suppressed the PGF2a-stimulated PGF2a production by luteal tissue, indicating that the PGF2a in the medium was of luteal origin. Consistent with these secreted-PGF2a profiles, PGF2a receptor (PTGFR) protein expression was higher during the mid and late luteal phases than at early and developing luteal phases. Treatment of cultured bovine luteal cells obtained from the mid luteal phase with PGF2a (1?M) significantly increased the expressions of PTGS2, PGF synthase (PGFS), and carbonyl reductase 1 (CBR1) at 24?h post-treatment. Together, these results suggest the presence of a local auto-amplification system for PGF2a mediated by PTGS2, PGFS, and CBR1 in the bovine CL, which may play an important role in luteolysis. Mol. Reprod. Dev. 2014 Wiley Periodicals, Inc.
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PGF2a is the primary hormonal signal that triggers luteal regression in many species. However, PGF2a was also reported to have luteotrophic actions (Miyamoto et al., 1993 and 1997; Alila et al., 1988) and its direct effects on luteal cells result in a marked elevation of agonist-stimulated cAMP and progesterone synthesis (Mamluk et al., 1999). Additionally, PGF2a acts on non-steroidogenic cells too, it causes the contraction of various smooth muscle cells (Kawarabashi et al., 1997) and stimulates the secretion of endothelin-1 from endothelial cells (Girsh et al., 1996).
Expression regulated by
LH, Steroids, PGF2a
Comment
Estrogen Promotes Luteolysis by Redistributing PGF2α Receptors Within Primate Luteal Cells. Kim SO et al. (2015) Prostaglandin F2α (PGF2α) has been proposed as a functional luteolysin in primates. However, administration of PGF2α or prostaglandin synthesis inhibitors in vivo both initiate luteolysis. These contradictory findings may reflect changes in PGF2α receptors (PTGFR) or responsiveness to PGF2α at a critical point during the life span of the corpus luteum. The current study addressed this question using ovarian cells and tissues from female cynomolgus monkeys and luteinizing granulosa cells from healthy women undergoing follicle aspiration. PTGFRs were present in the cytoplasm of monkey granulosa cells, while PTGFRs were localized to the perinuclear region of large, granulosa-derived monkey luteal cells by mid-late luteal phase. A PTGFR agonist decreased progesterone production by luteal cells obtained at mid-late and late luteal phases but did not decrease progesterone production by granulosa or luteal cells from younger corpora lutea. These findings are consistent with a role for perinuclear PTGFRs in functional luteolysis. This concept was explored using human luteinizing granulosa cells maintained in vitro as a model for luteal cell differentiation. In these cells, PTGFRs relocated from the cytoplasm to the perinuclear area in an estrogen- and estrogen receptor-dependent manner. Similar to our findings with monkey luteal cells, human luteinizing granulosa cells with perinuclear PTGFRs responded to a PTGFR agonist with decreased progesterone production. These data support the concept that PTGFR stimulation promotes functional luteolysis only when PTGFRs are located in the perinuclear region. Estrogen receptor-mediated relocation of PTGFRs within luteal cells may be a necessary step in the initiation of luteolysis in primates.//////////////////
Gonadotropins and cAMP (Tsai et al., 1996; Ristimaki et al., 1997; Mamluk et al., 1998) PGF2a and phorbol 12-myristate 13-acetate (Rueda et al., 1995; Vaananen et al., 1998; Mamluk et al., 1998) are the major regulators of FP receptors. The first upregulate while the latter downregulate PGF2a receptor expression. Therefore, within the corpus luteum, FP receptor increase soon after the LH surge and are reduced after exposure to PGF2a.
Ovarian localization
Oocyte, Luteal cells, endothelial cells
Comment
PGF2a receptor mRNA is expressed in corpus luteum soon after the LH surge (Wiltbank et al., 1995;Olofsson and Leung, 1996). All three major cell types of the bovine corpus luteum, small and large luteal cells as well as the resident endothelial cells, express the PGF2a receptor mRNA (Mamluk et al., 1998).
Follicle stages
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment: Mice lacking the gene encoding the receptor for prostaglandin F2alpha (FP) developed normally but were unable to deliver normal fetuses at term [(Sugimoto et al., 1997).$ Failure of parturition in mice lacking the prostaglandin F receptor. Sugimoto Y 1997 et al.
Mice lacking the gene encoding the receptor for prostaglandin F2alpha (FP) developed normally but were unable to deliver normal fetuses at term. Although these FP-deficient mice showed no abnormality in the estrous cycle, ovulation, fertilization, or implantation, they did not respond to exogenous oxytocin because of the lack of induction of oxytocin receptor (a proposed triggering event in parturition), and they did not show the normal decline of serum progesterone concentrations that precedes parturition. Ovariectomy at day 19 of pregnancy restored induction of the oxytocin receptor and permitted successful delivery in the FP-deficient mice. These results indicate that parturition is initiated when prostaglandin F2alpha interacts with FP in ovarian luteal cells of the pregnant mice to induce luteolysis.
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