Biol Reprod Track the topics, authors and articles important to you
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow My Folders
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Anderson, L. E.
Right arrow Articles by Wiltbank, M. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Anderson, L. E.
Right arrow Articles by Wiltbank, M. C.
Agricola
Right arrow Articles by Anderson, L. E.
Right arrow Articles by Wiltbank, M. C.
Biology of Reproduction 64, 1041-1047 (2001)
© 2001 Society for the Study of Reproduction, Inc.

Minireview

Prostaglandin F2{alpha} Receptor in the Corpus Luteum: Recent Information on the Gene, Messenger Ribonucleic Acid, and Protein1

Lori E. Andersona, Yuh-Lin Wua, Shaw-Jenq Tsaib, and Milo C. Wiltbank2,a

a Endocrinology-Reproductive Physiology Program and Department of Dairy Science, University of Wisconsin-Madison, Madison, Wisconsin 53706 b Department of Physiology, National Cheng Kung University, College of Medicine, Tainan 700, Taiwan ROC


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 CONCLUSIONS
 REFERENCES
 
The prostaglandin (PG) F2{alpha} 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 PGF2{alpha} 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 PGF2{alpha} based on three-dimensional modeling and comparisons with other G-protein-coupled receptors. Moieties of the PGF2{alpha} 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.

corpus luteum, FP receptor, gene regulation, ovary, PGF2{alpha}


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
CONCLUSIONS
 REFERENCES
 
Prostaglandins (PG) are modified fatty acids that were first isolated in the late 1950s [1]. The potential involvement of PG in luteal regression was first suggested in 1966 by Babcock in a discussion on bovine luteal maintenance [2]. The definitive role of PGF2{alpha} in luteal regression has been demonstrated by a variety of different methodologies in various species (recently reviewed by McCracken et al. [3]). The action of PGF2{alpha} appears to be primarily if not exclusively mediated by a plasma membrane receptor termed the FP receptor (FPr). Prostaglandin receptors are members of the seven-transmembrane-domain receptor superfamily. There appears to be a single gene that encodes the FPr, and the FPr mRNA has been cloned from mouse [4], rat [5, 6], sheep [7], cow [8], and human [6, 9]. Recently, knockout of the FPr in mice has demonstrated that normal luteal regression at the time of parturition does not occur in the absence of a functional FPr [10]. Activation of the FPr by PGF2{alpha} in a responsive corpus luteum (CL) initiates a cascade of intracellular pathways that result in luteolysis. This review will focus on recent information related to the structural and functional aspects of the gene, mRNA, and protein for the FPr.

Gene Structure and Regulation of FPr

The FPr gene structure (Fig. 1) has been evaluated in three mammalian species: human [11, 12], murine [13, 14], and bovine [15]. The gene size is approximately 10 (human), 11 (mouse), and 40 (cow) kilobases (kb). The mouse FPr gene has been mapped to the distal end of chromosome 3 and is located near the gene for the PGE receptor-subtype 3 [13, 16]. In humans, the genes for the FPr and PGE receptor-subtype 3 are localized to the short arm of chromosome 1 [11]. The genes for other PG receptors have been mapped to chromosomes 5 (PGE receptor-subtype 2) and 19 (PGE receptor-subtype 1, prostacyclin receptor, and thromboxane receptor) in humans [11] and to chromosomes 7 (prostacyclin receptor), 8 (PGE receptor-subtype 1), 10 (thromboxane receptor), 14 (PGD receptor), and 15 (PGE receptor-subtype 4) in mice [13, 16].



View larger version (20K):
[in this window]
[in a new window]
  		FIG. 1. Schematic illustration of the gene structure of the bovine, human, and mouse FPr. White rectangles indicate translated regions, and black rectangles represent untranslated regions of exons. Solid lines indicate introns and dotted lines depict the 5' flanking region. Shaded rectangles denote proposed promoter regions [12, 14, 15]

The exon/intron organization of the FPr gene (Fig. 1) is conserved among humans [12], mice [14], and cattle [15] and is similar to other prostanoid receptor genes [17]. The FPr gene consists of three exons and two introns with the translated region located in exons 2 and 3 [12, 14, 15]. The first exon is relatively short (160 to 194 base pairs [bp]) and includes most of the 5' untranslated region. Intron 1 ranges in size from 1.3 to 1.5 kb and may contain important promoter regions. The second exon (868 to 870 bp) contains an untranslated region of approximately 70 bp and the majority of the translated receptor. The large second intron (6.1 to 33 kb) interrupts the translated region at the sixth transmembrane domain [12, 14, 15]. The splice junction located in the sixth transmembrane domain is also conserved in other PG receptor genes, such as the human PGE receptor-subtype 3, prostacyclin receptor and thromboxane receptor [17]. The third exon (1066 to 3977 bp) includes the remainder of the translated region and a large untranslated region [12, 14, 15]. As discussed below, the region of the gene that codes for the receptor protein is highly conserved among species.

Multiple transcription initiation sites have been identified in the murine and bovine FPr. In the mouse, the major transcription start site is located at the 5' end of exon 1, 232 bp upstream of the ATG that marks the translation start site [14]. Several minor transcription start sites were found in exon 1 and the 5' flanking region (between 274 and 222 bp upstream of ATG) [14]. In the bovine FPr, multiple transcription initiation sites were identified in exon 1 (265 to 98 bp upstream of ATG; excludes intron 1). In addition, other minor transcription start sites were identified [15] in intron 1 (124 and 79 bp upstream of ATG; within intron 1). Transcription initiation sites have not yet been reported for the human FPr gene.

Promoter regulation of the FPr is not yet well characterized. In the human FPr gene, a 370-bp segment upstream of exon 1 was found to contain a probable promoter region 154 to 105 bp upstream of exon 1 [12]. It is conceivable that other areas of the 5' flanking region and intron 1 may contain promoter sites in the human FPr gene. Recent sequencing of the human genome should provide characterization of promoter regions.

A large region of the mouse FPr gene has been investigated for promoter activity [14]. The 5' flanking region contained two Sp1 (SV-40 protein) sites but lacked other typical elements such as TATA-like box, CAAT-like box, cAMP-responsive element (CRE), or estrogen-responsive element. Transgenic mice have been generated that express a 7.3-kb region of the FPr gene (encompassing the 5' flanking region, exon 1, intron 1, and the untranslated region of exon 2) connected to the lacZ reporter gene. Endogenous FPr mRNA was detected in the kidney, stomach, and corpora lutea of both normal and transgenic mice with expression in the corpus luteum 100-fold greater than in other tissues. Surprisingly, the transgene product, ß-galactosidase mRNA, was expressed in the kidney and stomach but was not expressed in the ovary [14]. Thus, the promoter for the FPr gene may differ for different tissues with regions other than the 7.3-kb region upstream of ATG being important for transcriptional regulation in the CL.

Two potential promoter regions were identified in the bovine FPr gene (Fig. 1) [15]. A 1.6-kb region upstream of exon 1 contained consensus sequences for the transcription factors: TRE/AP-1 (TPA-responsive element/activator protein-1), NF-IL6 (nuclear factor-interleukin 6), Sp1, and GCF (GC binding factor). The second potential promoter in intron 1 (1.2 kb) contained motifs for Sp1, TRE/AP-1, CRE, NF-IL6, and AP-2 (activator protein-2) as well as CAAT-like and TATA-like boxes [15]. Promoter activity of these two regions in the bovine FPr gene has been investigated in an in vitro assay [15]. Bovine luteal cells were transfected with an expression vector containing the two potential promoter regions linked to the luciferase gene. Activation of protein kinase C (PKC) by phorbol esters, but not activation of protein kinase A (PKA) by forskolin, stimulated an increase in luciferase activity in cells transfected with the 5' flanking promoter region and the reporter gene. Neither treatment altered luciferase activity in cells that contained the intron 1 promoter region and luciferase gene. This result is contradictory to the reported regulation of FPr mRNA in which forskolin treatment increased FPr mRNA [18, 19] and phorbol ester treatment decreased FPr mRNA [20]. Thus, it is likely that additional regions of the genome are needed to mediate physiological transcription of the FPr gene. We have transfected bovine granulosa cells with an expression plasmid containing the 3.3-kb 5' flanking region of the bovine FPr linked to luciferase (unpublished). Following 2 days of treatment with forskolin there was a >1000-fold increase in FPr mRNA but no change in luciferase expression. Negative results such as these are difficult to interpret, but another promoter, the prostaglandin G/H synthase-2 promoter, linked to luciferase was induced by forskolin in the same cells. Perhaps, as discussed above for the mouse, the 5' region is not sufficient for FPr promoter activity in the bovine CL. Thus, although the structure of the FPr gene is now well described, an understanding of the promoter regions for this gene has not been provided by initial studies using standard promoter analysis methods. Determination of the promoter regions used for this gene in the CL may provide unique insight into tissue-specific, hormonally regulated gene expression.

Messenger RNA for FPr

Expression of mRNA encoding for the FPr has been evaluated in a variety of tissues using Northern blot hybridization [4–8, 20–22] or quantitative, competitive reverse transcriptase-polymerase chain reaction [18, 23, 24]. The CL expresses levels of FPr mRNA at least 100-fold greater than any other ovine tissue [23], although some expression was also detected in ovarian stroma, adrenal medulla, lung, kidney medulla, and the inner myometrial layer. In situ hybridization revealed that expression of FPr mRNA was localized primarily to large luteal cells in ovine [20] or bovine midcycle CL [8, 21] or in CL from pregnant mouse ovaries [4].

Northern blot hybridization of luteal mRNA from various species identified a major FPr mRNA band between 4.1 to 6.1 kb [4–8, 20–22]. A shorter major band of 2.3 kb was also identified in the mouse [4]. Additional minor hybridizing bands ranging in size from 2 to 9.1 kb have been identified in various species [4–7, 20–22]. Recently, Pierce et al. [25] reported cloning of an alternatively spliced ovine FPr isoform (FPB) that is 45 amino acids shorter in the carboxyl terminal than the common FPr (FPA). The FPB isoform appears to be produced by splicing out a putative intron sequence of 3.2 kb in length that is retained in the FPA isoform [25]. Nonetheless, the authors state that FPA is the most abundant isoform in midcycle ovine CL, from which the FPB isoform was cloned. The physiological significance of FPr isoforms has not been completely elucidated.

The physiological regulation of FPr mRNA expression has been the focus of a number of recent investigations. As a general overview, there are very low concentrations of FPr in the ovary prior to ovulation. After ovulation there is a dramatic increase in FPr mRNA and protein in the CL. FPr remains elevated throughout most of the normal luteal phase and pregnancy but appears to decrease at luteolysis.

In vitro and in vivo studies have provided substantial insight into the initial induction of luteal FPr. In the preovulatory follicle there appears to be very little FPr mRNA expression in humans or cattle. As shown in Figure 2, the LH surge caused more than a 1000-fold increase in FPr mRNA concentration in the bovine CL in vivo [18]. In cultured granulosa cells, treatment with hCG dramatically increased FPr mRNA [18, 26]. This action appears to be mediated by PKA as evidenced by similar stimulation of FPr mRNA by forskolin or 8-bromo-cAMP, pharmacologic stimulators of the cAMP/PKA signaling pathway [18, 19, 26]. In addition, stimulation of FPr mRNA by hCG could be inhibited by the PKA inhibitor H89 (unpublished). The timing of PKA-mediated induction of FPr mRNA was surprisingly long (>24 h), suggesting that other protein products may be essential for this induction. Recently, it was shown that interleukin-1ß (IL-1ß) also induced FPr mRNA expression in human granulosa-luteal cells in vitro [27]. The effect of IL-1ß on FPr mRNA induction also requires 24 h and is additive with hCG, suggesting that they may act through different signaling pathways [27]. The physiological significance of FPr induction by the LH surge is probably related to forming a CL that has the capacity to regress in response to PGF2{alpha} at the end of the luteal life span. In the early CL, PGF2{alpha} action may be luteotropic rather than luteolytic. For example, treatment with PGF2{alpha} plus forskolin increased progesterone production [28] and cAMP production [29] in bovine luteinized theca and granulosa cells.



View larger version (24K):
[in this window]
[in a new window]
  		FIG. 2. In vivo temporal expression of FPr mRNA in bovine granulosa cells and CL. Ovaries were removed at various time points before and after ovulation to quantify FPr mRNA expression in follicles and CL (see Tsai et al. [18] for details). Different letters indicate significant differences (P < 0.05). n = 5 heifers per group

There also appear to be inhibitory pathways that regulate FPr mRNA expression in the CL. In vivo studies showed that PGF2{alpha} treatment decreased FPr mRNA in midcycle ovine CL [20, 22, 23] and in early (Day 4) and midcycle (Day 11) bovine CL [24]. An in vivo dose response study showed that low doses (3–10 mg PGF2{alpha} per 60 kg body weight) of PGF2{alpha} injected into the jugular vein caused a transient decrease in FPr mRNA while a high dose (30 mg PGF2{alpha} per 60 kg body weight) caused a more sustained (24 h) decrease in FPr mRNA in ovine midcycle CL [30]. During physiological luteal regression, there also is a dramatic decrease in ovine luteal FPr mRNA concentrations [7, 22]. Similarly, treatment with PGF2{alpha} in vitro decreased FPr mRNA in either bovine luteinized granulosa cells or ovine midcycle large luteal cells [19, 23]. In contrast, PGF2{alpha} treatment increased FPr mRNA in rat CL, suggesting some species variation in regulation of FPr expression [31]. Pharmacological agents, such as ionomycin or phorbol esters, that activate downstream effectors of PGF2{alpha}-mediated signaling reduce FPr mRNA expression in ovine luteal cells and human granulosa-lutein cells [23, 26]. Infusion of phorbol 12-myristate 13-acetate (PKC activator) into the ovarian artery also caused a decrease in FPr mRNA in the midcycle ovine CL at 4 and 12 h after infusion, further implicating the involvement of PKC in inhibition of FPr mRNA [20].

In summary, FPr induction following ovulation is clearly necessary for luteolysis to occur in the normal estrous cycle and pregnancy. Parturition does not occur in FPr knock-out mice, due to the absence of luteolysis associated with FPr activation [10]. The biological significance of PGF2{alpha}-mediated FPr mRNA down-regulation after the initiation of luteolysis is not yet clear. This action would tend to decrease expression of FPr mRNA and protein at the same time that receptors might be down-regulated by internalization and degradation mechanisms. It could be speculated that these mechanisms would tend to prevent overstimulation of cells at a time of high ligand concentrations. During pregnancy in cattle and sheep, FPr mRNA and protein remain high, suggesting that a decrease in FPr is not necessary for maternal recognition of pregnancy [21, 22, 32].

Protein for FPr

Sequence analysis of FPr cDNA in numerous species suggests that the protein belongs to the G-protein-coupled receptor superfamily. Hydropathy analysis [33] of the FPr from all species has identified seven hydrophobic regions that presumably represent transmembrane domains as illustrated in Figure 3, A and B.



View larger version (136K):
[in this window]
[in a new window]
  		FIG. 3. A) Model of the bovine FPr with respect to the cell membrane. Amino acids outlined in red are conserved in FPr of five species. Amino acids outlined in black are not conserved in FPr. Blue indicates amino acids that are highly conserved in all PG receptors. Green denotes potential PKC phosphorylation sites; * indicates potential N-glycosylation sites. Arginine-291 is proposed to form a Schiff base with the C1 carboxyl of PGF2{alpha} [36]. Histidine-81 may be involved in PGF2{alpha} binding through hydrogen bonding [40]. A disulfide bond likely forms between Cys-108 and Cys-186 that may stabilize the protein structure [6, 9, 38]. Proline-170, Pro-264, and Pro-301 in the fourth, sixth, and seventh transmembrane domains likely produce kinks in the structure that form a ligand binding pocket [35, 38, 43, 44]. B) A proposed arrangement of the transmembrane domains (TMD) of the FPr as viewed from the outside surface of the cell. Hydrophilic amino acids on the inside of the core form a ligand binding pocket for PGF2{alpha}. Hydrophobic amino acids on the outside of the seven helices associate with phospholipids in the plasma membrane. The approximate locations of Arg-291 and His-81 that may be involved in PGF2{alpha} binding are indicated. C) Chemical structure of PGF2{alpha} and inhibition constants (IC50) of PGs that differ from PGF2{alpha} at one site. [3H]PGF2{alpha} was inhibited by various nonradioactive PGs in bovine CL plasma membrane. Arrows indicate the site that the indicated nonradioactive PG differed from PGF2{alpha}. IC50 values for each PG are indicated in parentheses. Green arrows indicate critical sites for the binding of all PGs to PG receptors. Changes at the first carbon (PGF2{alpha} dimethyl amide or PGF2{alpha} isopropyl ester) or the 15th hydroxyl (15-keto PGF2{alpha}) dramatically decreased binding. Red arrows indicate the essential sites for FPr binding specificity. Changes at the C5/C6 double bond (PGF1{alpha} or 5-trans PGF2{alpha}) or at the C9 hydroxyl (PGE2) appear to be important for binding specificity in the FPr. Black arrows indicate that changes at these sites are not critical for specificity or binding to the FPr. Alterations at the C11 hydroxyl (PGD2) or at the C13/C14 double bond (13,14-dihydro-PGF2{alpha}) have little effect on specificity or binding [49]

The size of the FPr protein is similar among species, with estimated molecular weights ranging from 40 060 (human) to 40 983 Da (bovine) [8, 9]. The bovine and ovine FPr contain 362 amino acid residues in the open reading frame [7, 8], while mouse and rat FPr have 366 amino acids [4, 5], and the human FPr includes 359 amino acids [9]. Figure 3A shows the amino acid sequence for the bovine FPr with amino acids marked to indicate conservation in other PG receptors or in FPr from other species. The bovine FPr [8] shares 98% homology with the ovine FPr [7], 86% with the human FPr [9], 80% with the mouse FPr [4], and 78% with the rat FPr [5]. In these five species, 272 out of 362 amino acids (75.1%) in the FPr are identical (Fig. 3A).

The three-dimensional structure of bacteriorhodopsin revealed by electron cryomicroscopy [34] and mutational data on the ß2-adrenergic receptor have allowed construction of three-dimensional models for several mammalian G-protein-coupled receptors, including human thromboxane A2 (TXA2) receptor (TP) [35] and subsequently the bovine FPr [36]. Based on the fact that {alpha}-helices contain 3.6 residues per helical turn, sequence analysis shows that the transmembrane domains of G-protein-coupled receptors contain a predominance of hydrophobic residues on one side of each {alpha}-helix and hydrophilic residues on the other side (Fig. 3B) [37, 38]. It has been postulated that the hydrophilic residues of the seven helices face each other, thus forming a ligand binding pocket, while the hydrophobic residues face the lipid bilayer (Fig. 3B) [35, 37, 38]. Some amino acids located on the hydrophilic sides of the seventh transmembrane domain of G-protein-coupled receptors appear to be essential in ligand binding and are highly conserved in all PG receptors. It has been determined that retinal binds to lysine 296 in the seventh transmembrane domain of bovine visual rhodopsin via Schiff base formation [39]. A three-dimensional model for the human TP receptor suggests that arginine 295, analogous to lysine 296 in bovine visual rhodopsin, is exposed to the hydrophilic ligand binding pocket and is a likely candidate for binding TXA2 [35]. Likewise, arginine 291 in the FPr has been proposed to form a Schiff base with the carboxyl group of PGF2{alpha} (Fig. 3, A and B) [36]. Another amino acid, histidine 81, in the second transmembrane domain, may also be important for PGF2{alpha} binding as shown in transfection studies with mutant rat FPr expressed in COS-7 cells [40]. Molecular modeling suggests that histidine 81 is in close proximity to arginine 291 (Fig. 3B). The authors propose that histidine 81 is involved in PGF2{alpha} binding by acting as a hydrogen bond donor [40]. Sakamoto et al. [36] have also speculated that hydroxyl groups on the 9th and 11th carbons of PGF2{alpha} interact with serine or threonine residues in the third and seventh transmembrane domains based on the three-dimensional model. Future point mutation analyses of the PG receptors may indicate the key amino acids involved in receptor-ligand interaction and receptor specificity.

Several other amino acids that are conserved among the FPr of different species are worth noting (see Fig. 3A). As observed in other G-protein-coupled receptors [38], two potential N-glycosylation sites (Asn-4 and Asn-19) are found in the amino-terminal region of the FPr [4–9]. Six serine or threonine residues in the FPr have been suggested as potential phosphorylation sites by PKC [5, 6, 8, 9, 41]. Two of these are in the second intracellular loop (Ser-144 and Thr-148) while four are found in the COOH-terminal end (Thr-319, Ser-337, Ser-341, and Thr-353) of the receptor. Cysteine residues (Cys-108 and Cys-186) in the first and second extracellular loops of the FPr likely form a disulfide bond that stabilizes the protein structure [6, 9, 38]. These two cysteines are highly conserved among all PG receptors [36, 42] and many other G-protein-coupled receptors [38]. Three prolines in transmembrane domains IV, VI, and VII (Pro-170, Pro-264, and Pro-301) likely introduce kinks in the {alpha}-helices and may be essential in forming a ligand binding pocket [35, 38, 43, 44].

Binding Specificity of FPr

One high affinity binding site with a 50% inhibitory concentration (IC50) ranging from 2.5 nM [4] to 40 nM [7] has been reported in studies analyzing binding of [3H]PGF2{alpha} to luteal plasma membranes or luteal cells. Some investigators have also reported a second low affinity site on small luteal cells (240–3100 nM) [45–48]. The results from our pharmacological analysis of displacement of [3H]PGF2{alpha} binding to bovine luteal plasma membranes are summarized in Figure 3C [49]. It is clear that there is some cross-reactivity between various PGs and specific PG receptors, although the extent of this cross-reactivity varies among different species and studies [49, 50, 51]. The cross-reactivity of PGs and PG receptors is due in part to similarity in structure of the PG molecules. There are certain key sites, such as the C1 carboxylic acid and the C15 hydroxyl, that are identical in other PGs and appear to be essential for binding to any PG receptors. Sites that differ between PGs, such as C9 and C11, are likely to be critical for specificity of receptor binding. As shown in Figure 3C, displacement studies using PGs that differ subtly from PGF2{alpha} have been used to identify sites that are essential for binding and for specificity of the FPr.

As discussed above, the C1 carboxylic acid appears to form a Schiff base with an arginine in the seventh transmembrane domain that is ubiquitous to all PG receptors. In an early study, Kimball and Lauderdale [52] showed that PGF2{alpha} methyl ester reduced relative binding to 26.3% compared to PGF2{alpha}, and we found dramatic reductions in binding with PGF2{alpha} dimethyl amide and PGF2{alpha} isopropyl ester [49].

The C15 position is critical in PG metabolism because inactivation of PGs occurs by enzymatic dehydrogenation of C15 by 15-hydroxy-prostaglandin dehydrogenase present in lung, liver, kidney [53], and recently reported at high levels in the CL [54]. Changing the hydroxyl at the 15th carbon to 15-keto PGF2{alpha} or 15-methyl PGF2{alpha} greatly decreased binding affinity to the FPr [49]. A similar decrease in binding was observed using 15-epi-PGE1 and 15-keto-PGE1 to inhibit [3H]PGE1 [55]. Surprisingly, dramatic alterations in PGF2{alpha} between C17 and C20 appear to have little impact on binding affinity. In fact, FPr agonists with phenyl groups attached between C17 and C20 appear to have longer half-lives in vivo [56, 57].

The obvious differences in the C9 and C11 position between the primary PGs has led to the idea that these positions provide the critical interactions producing specificity between specific PGs and their receptors. Surprisingly, alteration of the hydroxyl at the C11 position to a ketone group (PGD2) or removal of the hydroxyl (11-deoxy-PGF2{alpha}) produced little change in binding affinity in our studies with bovine luteal membranes (Fig. 3C). The human FPr expressed in COS cells [9] also had similar IC50s for PGF2{alpha} (3 nM) and PGD2 (7 nM). However, other binding studies with cow, mouse, or rat FPr found IC50 values of 300 to 500 nM for PGD2 [4, 6, 8, 48]. The species-specific or technical reasons for these differing results with binding of PGD2 to the FPr remain unresolved. Interestingly, substitution of the C11 hydroxyl with fluoride produces a potent and specific antagonist from a PGF2{alpha} analogue [50]. In contrast, changing the C9 hydroxyl group in PGF2{alpha} to a ketone (PGE2) produced a 10-fold [49, 55, 58] increase in the IC50. Not surprisingly, the ketone group at the ninth carbon of PGE2 was also key in high affinity binding to the luteal EP receptor [49, 55, 58]. It is likely that the ketone or hydroxyl groups on the ninth carbon confer partial specificity by interacting with distinct amino acids in their respective PG receptors. The double bond between the fifth and sixth carbon also appears to be essential for FPr binding and specificity. Changing this site to a single bond (PGF1{alpha}) or altering the conformation of the bond from cis to trans (5-trans PGF2{alpha}) dramatically decreased inhibition of [3H]PGF2{alpha} binding [49, 52, 55, 58]. Interestingly, this bond does not appear to alter the binding of PGE1 or PGE2 to the EP receptor in CL [49, 55]. Alteration of two critical sites on the PGF2{alpha} molecule, such as found in PGE1 that contains both a ketone at C9 and a single bond at C5/C6, eliminates binding to the FPr (IC50 > 10 000 nM).

Binding of PGF2{alpha} to the FPr activates numerous intracellular effector systems, including: the trimeric G-proteins G{alpha}q and G{alpha}11 [59], the small G-protein Rho [60], phospholipase C [61, 62], inositol triphosphate/free intracellular calcium [63, 64], phospholipase D [65], and mitogen-activated protein kinases [66, 67]. Other manuscripts [3, 68] have reviewed events that occur after binding of PGF2{alpha}, and this minireview will not attempt to examine this extensive literature.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 CONCLUSIONS
REFERENCES
 
Substantial progress has been made in understanding the action of PGF2{alpha} and its receptor in the CL. Some of the key progress in the 1990s has been in resolution of the gene, mRNA, and protein sequences for the FPr from many species, characterization of hormonal regulation of FPr mRNA, and determination of key intracellular responses to PGF2{alpha} binding. Many critical issues remain unresolved such as the molecular mechanisms that regulate FPr gene transcription in the CL and the crucial interactions involved in the binding and activation of the FPr by PGF2{alpha}.


   FOOTNOTES
 
First decision: 30 August 2000.

1 Supported by National Institutes of Health grant HD-32623. Back

2 Correspondence: Milo C. Wiltbank, University of Wisconsin-Madison, 236 Animal Science Building, 1675 Observatory Drive, Madison, WI 53706. FAX: 608 263 9412; wiltbank{at}calshp.cals.wisc.edu Back

Accepted: November 1, 2000.

Received: August 9, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 CONCLUSIONS
 REFERENCES
 

  1. Bergström S, Sjövall J. The isolation of prostaglandin. Acta Chem Scand 1957; 11:1086.
  2. Babcock JC. Luteotrophic and luteolytic mechanisms in bovine corpora lutea. J Reprod Fertil 1966; (suppl 1):47.
  3. McCracken JA, Custer EE, Lamsa JC. Luteolysis: a neuroendocrine-mediated event. Physiol Rev 1999; 79:263–324.[Abstract/Free Full Text]
  4. Sugimoto Y, Hasumoto K, Namba T, Irie A, Katsuyana M, Negishi M, Kakizuka A, Narumiya S, Ichikawa A. Cloning and expression of a cDNA for mouse prostaglandin F receptor. J Biol Chem 1994; 269:1356–1360.[Abstract/Free Full Text]
  5. Kitanaka J, Hashimoto H, Sugimoto Y, Negishi M, Aino A, Gotoh M, Ichikawa A, Baba A. Cloning and expression of a cDNA for rat prostaglandin F2{alpha} receptor. Prostaglandins 1994; 48:31–41.[CrossRef][Medline]
  6. Lake S, Gullberg H, Wahlqvist J, Sjögren A-M, Kinhult A, Lind P, Hellström-Lindahl E, Stjernschantz J. Cloning of the rat and human prostaglandin F2{alpha} receptors and the expression of the rat prostaglandin F2{alpha} receptor. FEBS Lett 1994; 355:317–325.[CrossRef][Medline]
  7. Graves PE, Pierce KL, Bailey TJ, Rueda BR, Gil W, Woodward DF, Yool AJ, Hoyer PB, Regan JW. Cloning of a receptor for prostaglandin F2{alpha} from the ovine corpus luteum. Endocrinology 1995; 136:3430–3436.[Abstract]
  8. Sakamoto K, Ezashi T, Miwa K, Okuda-Ashitaka E, Houtani T, Sugimoto T, Ito S, Hayaishi O. Molecular cloning and expression of a cDNA of the bovine prostaglandin F2{alpha} receptor. J Biol Chem 1994; 269:3881–3886.[Abstract/Free Full Text]
  9. Abramovitz M, Boie Y, Nguyen T, Rushmore TH, Bayne MA, Metters KM, Slipetz DM, Grygorczyk R. Cloning and expression of a cDNA for the human prostanoid FP receptor. J Biol Chem 1994; 269:2632–2636.[Abstract/Free Full Text]
  10. Sugimoto Y, Yamasaki A, Segi E, Tsuboi K, Aze Y, Nishimura T, Oida H, Yoshida N, Tanaka T, Katsuyama M, Hasumoto K, Murata T, Hirata M, Ushikubi F, Negishi M, Ichikawa A, Narumiya S. Failure of parturition in mice lacking the prostaglandin F receptor. Science 1997; 277:681–683.[Abstract/Free Full Text]
  11. Duncan AMV, Anderson LL, Funk CD, Abramovitz M, Adam M. Chromosomal localization of the human prostanoid receptor gene family. Genomics 1995; 25:740–742.[CrossRef][Medline]
  12. Betz R, Lagercrantz J, Kedra D, Dumanski JP, Nordenskjöld A. Genomic structure, 5' flanking sequences, and precise localization of 1p31.1 of the human prostaglandin F receptor gene. Biochem Biophys Res Commun 1999; 254:413–416.[CrossRef][Medline]
  13. Ishikawa T-O, Tamai Y, Rochelle J, Hirata M, Namba T, Sugimoto Y, Ichikawa A, Narumiya S, Taketo M, Seldin M. Mapping of the genes encoding mouse prostaglandin D, E, and F and prostacyclin receptors. Genomics 1996; 32:285–288.[CrossRef][Medline]
  14. Hasumoto K, Sugimoto Y, Gotoh M, Segi E, Yamasaki A, Yamaguchi M, Honda H, Hirai H, Negishi M, Kakizuka A, Ichikawa A. Characterization of the mouse prostaglandin F receptor gene: a transgenic mouse study of a regulatory region that controls its expression in the stomach and kidney but not in the ovary. Genes Cells 1997; 2:571–580.[Abstract]
  15. Ezashi T, Sakamoto K, Miwa K, Okuda-Ashitaka E, Ito S, Hayaishi O. Genomic organization and characterization of the gene encoding bovine prostaglandin F2{alpha} receptor. Gene 1996; 190:271–278.
  16. Taketo M, Rochelle JM, Sugimoto Y, Namba T, Honda A, Negishi M, Ichikawa A, Narumiya S, Seldin MF. Mapping of the genes encoding mouse thromboxane A2 receptor and prostaglandin E receptor subtype EP2 and EP3. Genomics 1994; 19:585–588.[CrossRef][Medline]
  17. Ogawa Y, Tanaka I, Inoue M, Yoshitake Y, Isse N, Nakagawa O, Usui T, Itoh H, Yoshimasa T, Narumiya S, Nakao K. Structural organization and chromosomal assignment of the human prostacyclin receptor gene. Genomics 1995; 27:142–148.[CrossRef][Medline]
  18. Tsai SJ, Wiltbank MC, Bodensteiner KJ. Distinct mechanisms regulate induction of messenger ribonucleic acid for prostaglandin G/H synthase-2, PGE (EP3) receptor, and PGF2{alpha} receptor in bovine preovulatory follicles. Endocrinology 1996; 137:3348–3355.[Abstract]
  19. Mamluk R, Chen D, Greber Y, Davis JS, Meidan R. Characterization of messenger ribonucleic acid expression for prostaglandin F2{alpha} and luteinizing hormone receptors in various bovine luteal cell types. Biol Reprod 1998; 58:849–856.[Abstract/Free Full Text]
  20. Juengel JL, Wiltbank MC, Meberg BM, Niswender GD. Regulation of steady-state concentrations of messenger ribonucleic acid encoding prostaglandin F2{alpha} receptor in ovine corpus luteum. Biol Reprod 1996; 54:1096–1102.[Abstract]
  21. Sakamoto K, Miwa K, Ezashi T, Okuda-Ashitaka E, Okuda K, Houtani T, Sugimoto T, Itos S, Hayaishi O. Expression of mRNA encoding the prostaglandin F2{alpha} receptor in bovine corpora lutea throughout the oestrous cycle and pregnancy. J Reprod Fertil 1995; 103:99–105.[Abstract/Free Full Text]
  22. Rueda BR, Botros IW, Pierce KL, Regan JW, Hoyer PB. Comparison of mRNA levels for the PGF2{alpha} receptor (FP) during luteolysis and early pregnancy in the ovine corpus luteum. Endocrine 1995; 3:781–787.[CrossRef]
  23. Tsai SJ, Anderson LE, Juengel JL, Niswender GD, Wiltbank MC. Regulation of prostaglandin F2{alpha} and E receptor mRNA by prostaglandin F2{alpha} in ovine corpora lutea. J Reprod Fertil 1998; 114:69–75.[Abstract/Free Full Text]
  24. Tsai SJ, Wiltbank MC. Prostaglandin F2{alpha} regulates distinct physiological changes in early and mid-cycle bovine corpora lutea. Biol Reprod 1998; 58:346–352.[Abstract/Free Full Text]
  25. Pierce KL, Bailey TJ, Hoyer PB, Gil DW, Woodward DF, Regan JW. Cloning of a carboxyl-terminal isoform for the prostanoid FP receptor. J Biol Chem 1997; 272:883–887.[Abstract/Free Full Text]
  26. Ristimäki A, Jaatinen R, Ritvos O. Regulation of prostaglandin F2{alpha} receptor expression in cultured human granulosa-luteal cells. Endocrinology 1997; 138:191–195.[Abstract/Free Full Text]
  27. Narko K, Ritvos O, Ristimäki A. Induction of cyclooxygenase-2 and prostaglandin F2{alpha} receptor expression by interleukin-1ß in cultured human granulosa-luteal cells. Endocrinology 1997; 138:3638–3644.[Abstract/Free Full Text]
  28. Meidan R, Aberdam E, Aflalo L. Steroidogenic enzyme content and progesterone induction by cyclic adenosine 3',5'-monophosphate-generating agents and prostaglandin F2{alpha} in bovine theca and granulosa cells luteinized in vitro. Biol Reprod 1992; 46:786–792.[Abstract]
  29. Mamluk R, Defer N, Hanoune J, Meidan R. Molecular identification of adenylyl cyclase 3 in bovine corpus luteum and its regulation by prostaglandin F2{alpha}-induced signaling pathways. Endocrinology 1999; 140:4601–4608.[Abstract/Free Full Text]
  30. Juengel JL, Haworth JD, Rollyson MK, Silva PJ, Sawyer HR, Niswender GD. Effect of dose of prostaglandin F2{alpha} on steroidogenic components and oligonucleosomes in ovine luteal tissue. Biol Reprod 2000; 62:1047–1051.[Abstract/Free Full Text]
  31. Olofsson JI, Leung CH, Bjurulf E, Ohno T, Selstam G, Peng C, Leung PC. Characterization and regulation of a mRNA encoding the prostaglandin F2{alpha} receptor in the rat ovary. Mol Cell Endocrinol 1996; 123:45–52.[CrossRef][Medline]
  32. Wiepz GJ, Wiltbank MC, Nett TM, Niswender GD, Sawyer HR. Receptors for prostaglandins F2{alpha} and E2 in ovine corpora lutea during maternal recognition of pregnancy. Biol Reprod 1992; 47:984–991.[Abstract]
  33. Kyte J, Doolittle RF. A simple method for displaying the hydropathic character of a protein. J Mol Biol 1982; 157:105–132.[CrossRef][Medline]
  34. Henderson R, Baldwin, JM, Ceska TA, Zemlin F, Beckmann E, Downing KH. Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy. J Mol Biol 1990; 213:899–929.[Medline]
  35. Yamamoto Y, Kamiya K, Terao S. Modeling of human thromboxane A2 receptor and analysis of the receptor-ligand interation. J Med Chem 1993; 36:820–825.[CrossRef][Medline]
  36. Sakamoto K, Kamimura M, Kurozumi S, Ito S. Prostaglandin F2{alpha} receptor. J Lipid Mediat Cell Signal 1995; 12:405–411.[CrossRef][Medline]
  37. Engelman D, Zaccai G. Bacteriorhodopsin is an inside-out protein. Proc Natl Acad Sci U S A 1980; 77:5894–5898.[Abstract/Free Full Text]
  38. Probst WC, Snyder LA, Schuster DI, Brosius J, Sealfon SC. Sequence alignment of the G-protein coupled receptor superfamily. DNA Cell Biol 1992; 11:1–20.[Medline]
  39. Thomas DD, Stryer L. Transverse location of the retinal chromophore of rhodopsin in rod outer segment disc membranes. J Mol Biol 1982; 154:145–157.[CrossRef][Medline]
  40. Rehwald M, Neuschäfer-Rube F, de Vries C, Püschel GP. Possible role for ligand binding of histidine 81 in the second transmembrane domain of the rat prostaglandin F2{alpha} receptor. FEBS Lett 1999; 443:357–362.[CrossRef][Medline]
  41. Fujino H, Srinivasan D, Pierce KL, Regan JW. Differential regulation of prostaglandin F2{alpha} receptor isoforms by protein kinase C. Mol Pharmacol 2000; 57:353–358.[Abstract/Free Full Text]
  42. Coleman RA, Smith WL, Narumiya S. VIII. International Union of Pharmacology classification of prostanoid receptors: properties, distribution and structure of the receptors and their subtypes. Pharmacol Rev 1994; 46:205–229.[Medline]
  43. Applebury ML, Hargrave PA. Molecular biology of the visual pigments. Vision Res 1986; 26:1881–1895.[CrossRef][Medline]
  44. Findlay J, Eliopoulos E. Three-dimensional modelling of G protein-linked receptors. Trends Pharmacol Sci 1990; 11:492–499.[CrossRef][Medline]
  45. Balapure AK, Caicedo IC, Kawada K, Watt DS, Rexroad CE Jr, Fitz TA. Multiple classes of prostaglandin F2{alpha} binding sites in subpopulations of ovine luteal cells. Biol Reprod 1989; 41:385–392.[Abstract]
  46. Gadsby JE, Balapure AK, Britt JH, Fitz TA. Prostaglandin F2{alpha} receptors on enzyme-dissociated pig luteal cells throughout the estrous cycle. Endocrinology 1990; 126:787–795.[Abstract/Free Full Text]
  47. Gadsby JE, Lovda JA, Britt JH, Fitz TA. Prostaglandin F2{alpha} receptor concentrations in corpora lutea of cycling, pregnant and pseudopregnant pigs. Biol Reprod 1993; 49:604–608.[Abstract]
  48. Sharif NA, Xu SX, Williams GW, Crider JY, Griffin BW, Davis TL. Pharmacology of [3H]PGE1/[3H]PGE2 and [3H]PGF2{alpha} binding to EP3 and FP prostaglandin receptor binding sites in bovine corpus luteum: characterization and correlation with functional data. J Pharmacol Exp Ther 1998; 286:1094–1102.[Abstract/Free Full Text]
  49. Anderson LE, Schultz MK, Wiltbank MC. Prostaglandin moieties that determine receptor binding specificity in the bovine corpus luteum. J Reprod Fertil 1999; 115:133–141.[Abstract/Free Full Text]
  50. Griffin BW, Williams GW, Crider JY, Sharif NA. FP prostaglandin receptors mediating inositol phosphates generation and calcium mobilization in Swiss 3T3 cells: a pharmacological study. J Pharmacol Exp Ther 1997; 281:845–854.[Abstract/Free Full Text]
  51. Kiriyama M, Ushikubi F, Kobayashi T, Hirata M, Sugimoto Y, Narumiya S. Ligand binding specificities of the eight types and subtypes of mouse prostanoid receptors expressed in Chinese hamster ovary cells. Br J Pharmacol 1997; 122:217–224.[CrossRef][Medline]
  52. Kimball FA, Lauderdale JW. Comparison of luteolytic effectiveness of several prostaglandin analogs in heifers and relative binding affinity for bovine luteal prostaglandin binding sites. Prostaglandins 1976; 12:985–995.[CrossRef][Medline]
  53. Änggård EE, Samuelsson B. Metabolism of prostaglandin E in guinea-pig lung: the structures of two metabolites. J Biol Chem 1964; 239:4097–4102.[Free Full Text]
  54. Silva PJ, Juengel JL, Turzillo AM, Rollyson MK, Niswender GD. Prostaglandin metabolism in the ovine corpus luteum: catabolism of prostaglandin F2{alpha} coincides with resistance of the corpus luteum to F2{alpha}. Biol Reprod 2000; 63:1229–1236.[Abstract/Free Full Text]
  55. Oien HG, Mandel LR, Humes JL, Taug D, Hoffsommer RD, Kuehl FA Jr. Structural requirements for the binding of prostaglandins. Prostaglandins 1975; 9:985–995.[CrossRef][Medline]
  56. Miller WL, Weeks JR, Lauderdale JW, Kirton KT. Biological activities of 17-phenyl-18,19,20-trinorprostaglandins. Prostaglandins 1975; 9:9–18.[CrossRef][Medline]
  57. Granström E. Metabolism of 17-phenyl-18,19,20-trinor-prostaglandin F2{alpha} in the cynomolgus monkey and the human female. Prostaglandins 1975; 9:19–45.[CrossRef][Medline]
  58. Kimball FA, Lauderdale JW. Prostaglandin E1 and F2{alpha} specific binding in the bovine corpora lutea: comparison with luteolytic effects. Prostaglandins 1975; 10:313–331.[Medline]
  59. Carrasco MP, Asbóth G, Phaneuf S, Bernal AL. Activation of the prostaglandin FP receptor in human granulosa cells. J Reprod Fertil 1997; 111:309–317.[Abstract/Free Full Text]
  60. Pierce KL, Fujino H, Srinivasan D, Regan JW. Activation of FP prostanoid receptor isoforms leads to Rho-mediated changes in cell morphology and in the cell cytoskeleton. J Biol Chem 1999; 274:35944–35949.[Abstract/Free Full Text]
  61. Gusovsky F. Prostaglandin receptors in NIH 3T3 cells: coupling of one receptor to adenylate cyclase and of a second receptor to phospholipase C. Mol Pharmacol 1991; 40:633–638.[Abstract]
  62. Boiti C, Zerani M, Zampini D, Gobbetti A. Nitric oxide synthase activity and progesterone release by isolated corpora lutea of rabbits in the early and mid-luteal phases of pseudopregnancy are modulated differently by prostaglandin E2 and prostaglandin F2{alpha} via adenylate cyclase and phospholipase C. J Endocrinol 2000; 164:179–186.[Abstract]
  63. Davis JS, Weakland LL, Weiland DA, Farese RV, West LA. Prostaglandin F2{alpha} stimulates phosphatidylinositol 4,5-biphosphate hydrolysis and mobilizes intracellular calcium in bovine luteal cells. Proc Natl Acad Sci U S A 1987; 84:3728–3732.[Abstract/Free Full Text]
  64. Wiltbank MC, Guthrie PB, Mattson MP, Kater SB, Niswender GD. Hormonal regulation of free intracellular calcium concentrations in small and large ovine luteal cells. Biol Reprod 1989; 41:771–778.[Abstract]
  65. Liu B, Nakashima N, Ito S, Nozawa Y. PLD activation in Chinese hamster ovary cells transfected with PG F2{alpha} receptor cDNA. Prostaglandins 1996; 51:233–248.[CrossRef][Medline]
  66. Hakeda Y, Shiokawa M, Shiokawa M, Mano H, Kameda T, Raisz LG, Kumegawa M. Prostaglandin F2{alpha} stimulates tyrosine phosphorylation and mitogen-activated protein kinase in osteoblastic MC3T3-E1 cells via protein kinase C activation. Endocrinology 1997; 138:1821–1828.[Abstract/Free Full Text]
  67. Chen D-B, Westfall SD, Fong HW, Roberson MS, Davis JS. Prostaglandin F2{alpha} stimulates the Raf/MEK1/mitogen-activated protein kinase signaling cascade in bovine luteal cells. Endocrinology 1998; 139:3876–3885.[Abstract/Free Full Text]
  68. Niswender GD, Juengel JL, Silva PJ, Rollyson MK, McIntush EW. Mechanisms controlling the function and life span of the corpus luteum. Physiol Rev 2000; 80:1–29.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
K. S. Song, Y. H. Choi, J.-M. Kim, H. Lee, T.-J. Lee, and J.-H. Yoon
Suppression of prostaglandin E2-induced MUC5AC overproduction by RGS4 in the airway
Am J Physiol Lung Cell Mol Physiol, April 1, 2009; 296(4): L684 - L692.
[Abstract] [Full Text] [PDF]

Home page
 ReproductionHome page
K. Shirasuna, S. Watanabe, T. Asahi, M. P B Wijayagunawardane, K. Sasahara, C. Jiang, M. Matsui, M. Sasaki, T. Shimizu, J. S Davis, et al.
Prostaglandin F2{alpha} increases endothelial nitric oxide synthase in the periphery of the bovine corpus luteum: the possible regulation of blood flow at an early stage of luteolysis
Reproduction, April 1, 2008; 135(4): 527 - 539.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
D. C. Wathes, D. R. E. Abayasekara, and R. J. Aitken
Polyunsaturated Fatty Acids in Male and Female Reproduction
Biol Reprod, August 1, 2007; 77(2): 190 - 201.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. Rosiansky-Sultan, E. Klipper, K. Spanel-Borowski, and R. Meidan
Inverse Relationship between Nitric Oxide Synthases and Endothelin-1 Synthesis in Bovine Corpus Luteum: Interactions at the Level of Luteal Endothelial Cell
Endocrinology, November 1, 2006; 147(11): 5228 - 5235.
[Abstract] [Full Text] [PDF]

Home page
 ReproductionHome page
S. Verma-Kumar, S V Srinivas, P Muraly, V. K Yadav, and R Medhamurthy
Cloning of a buffalo (Bubalus bubalis) prostaglandin F2{alpha} receptor: changes in its expression and concentration in the buffalo cow corpus luteum
Reproduction, June 1, 2004; 127(6): 705 - 715.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
J. D. Hennebold
Characterization of the ovarian transcriptome through the use of differential analysis of gene expression methodologies
Hum. Reprod. Update, May 1, 2004; 10(3): 227 - 239.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. A. Arosh, S. K. Banu, P. Chapdelaine, E. Madore, J. Sirois, and M. A. Fortier
Prostaglandin Biosynthesis, Transport, and Signaling in Corpus Luteum: A Basis for Autoregulation of Luteal Function
Endocrinology, May 1, 2004; 145(5): 2551 - 2560.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. Kawaminami, Y. Shibata, A. Yaji, S. Kurusu, and I. Hashimoto
Prolactin Inhibits Annexin 5 Expression and Apoptosis in the Corpus Luteum of Pseudopregnant Rats: Involvement of Local Gonadotropin-Releasing Hormone
Endocrinology, August 1, 2003; 144(8): 3625 - 3631.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. A. Arosh, S. K. Banu, P. Chapdelaine, V. Emond, J. J. Kim, L. A. MacLaren, and M. A. Fortier
Molecular Cloning and Characterization of Bovine Prostaglandin E2 Receptors EP2 and EP4: Expression and Regulation in Endometrium and Myometrium during the Estrous Cycle and Early Pregnancy
Endocrinology, July 1, 2003; 144(7): 3076 - 3091.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
V. A. Cavicchio, J. K. Pru, B. S. Davis, J. S. Davis, B. R. Rueda, and D. H. Townson
Secretion of Monocyte Chemoattractant Protein-1 by Endothelial Cells of the Bovine Corpus Luteum: Regulation by Cytokines But Not Prostaglandin F2{alpha}
Endocrinology, September 1, 2002; 143(9): 3582 - 3589.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow My Folders
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Anderson, L. E.
Right arrow Articles by Wiltbank, M. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Anderson, L. E.
Right arrow Articles by Wiltbank, M. C.
Agricola
Right arrow Articles by Anderson, L. E.
Right arrow Articles by Wiltbank, M. C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS