Prostaglandins, thromboxanes, and leukotrienes are oxygenated metabolites of arachidonic acid that are thought to act
through 7-transmembrane domain-type receptors. Prostaglandin E2 activates 4
receptors, designated prostaglandin E receptor subtypes EP1 through EP4.
General function
Receptor
Comment
Efficient synthesis of a novel m-phenylene derivative as a selective EP(4) agonist inducing follicular growth and maturation in the ovary. Hayashi R et al. An efficient and straightforward synthesis of a novel m-phenylene derivative has been developed. The optically pure dibromo compound was selected as a starting material. Through a protocol involving the Prins reaction and two steps of the Horner-Wadsworth-Emmons reaction, the basic skeleton was constructed with appropriate alpha and omega side chains. The compound proved to be a highly selective EP(4) agonist and a possible drug candidate for maturation of the uterine cervix.
The selective prostaglandin EP4 agonist, APS-999 Na, induces follicular growth and maturation in the rat ovary El-Nefiawy N, et al .
OBJECTIVE: It is known that prostaglandin E2 (PGE2) plays a crucial role in the ovulation process. PGE2 mediates its actions through four subtypes of receptors designated EP1-EP4. However, the nature of the ovulation-promoting effect of PGE2 is not well understood. We have carried out this in vivo research utilizing a new selective EP4 receptor agonist (EP4A; APS-999 Na) to investigate its role in folliculogenesis aiming at more understanding of the biological mechanism of action of PGE2. DESIGN AND METHODS: Immature, 22 day old Wistar rats were used. Animals were injected once either with placebo, 20 IU pregnant mare serum gonadotrophin (PMSG), or EP4A (10, 20 or 50 mug). In other experiments, EP4A was injected in PMSG stimulated rats. Ovarian follicle growth and development was assessed through total count and size measurement of ovulatory follicles in whole ovaries of the investigated groups. Utilizing immunohistochemistry, the spatial localization of the EP4 receptor in immature rat ovary and IL-8 pattern of expression after EP4A injection was also investigated. RESULTS: Our study showed that injection of EP4A resulted in increased follicle growth and development compared with the control, in a time- and dose-dependent manner. The highest values for follicle count and size were observed 12 and 24 h after EP4A injection. EP4A induced follicle growth with morphological characteristics similar to that induced by the standard PMSG. Most dense immune staining for EP4 receptor was noticed in proliferating granulosa cells of the secondary follicles while those of the primordial and primary follicles were not stained. EP4A injection induced the expression of IL-8 in the follicles. CONCLUSIONS: Our study revealed that: (i) the localization of EP4 receptor in the ovary implies a role in follicle growth, (ii) PGE2 induced ovarian follicle growth and development is mediated at least in part through the EP4 receptor, (iii) the action of EP4A is mediated through IL-8 up regulation and (iv) the new EP4A could be a promising reagent for various systems used to induce follicle maturation in clinical or agricultural fields. This knowledge may provide useful targets for manipulation of infertility.
Cyclooxygenase-2 derived prostaglandin E2 directs oocyte maturation by differentially influencing multiple signaling pathways. Takahashi T et al. The process of oocyte maturation which impacts ovulation and fertilization is complex and requires an integration of the endocrine, paracrine, juxtacrine and autocrine signaling pathways. This process involves an intimate interaction between the oocyte and encircling cumulus cells within a follicle, a unique venue for somatic and germ cell communication. Cumulus cell expansion and resumption of meiosis with germinal vesicle breakdown (GVBD) are major events in oocyte maturation. Cyclooxygenase-2 (COX-2) derived prostaglandin E2 (PGE2) is a known critical mediator of oocyte maturation, but the diverse function of this lipid mediator in oocyte maturation, ovulation and fertilization has not been fully appreciated. We show here that gonadotropins in coordination with PGE2 signaling via its cell surface G-protein coupled EP2 and EP4 receptor subtypes directs cumulus cell expansion and survival, and oocyte meiotic maturation by differentially impacting PKA, MAPK, NF-B and PI3K/Akt pathways. This study is unique in the sense that it provides evidence for new site- and event-specific involvement of these signaling pathways under the influence of COX-2 derived PGE2 during the critical stages of this somatic-germ cell interaction, an absolute requirement for oocyte maturation.
Expression regulated by
Growth Factors/ cytokines
Comment
Narko K, et al reported regulated expression of prostaglandin e(2) receptors ep2 and ep4 in human ovarian granulosa-luteal cells.
Prostaglandins (PGs) have been implicated in regulation of ovarian function. Transcripts for PGE(2) receptor subtypes EP2 and EP4 are expressed in freshly isolated human granulosa cells and in mouse ovaries as detected by Northern blot analysis. However, EP2 and EP4 receptor mRNA levels were low or nondetectable in cultured human granulosa luteal (GL) cells suggesting that these transcripts may be under hormonal and/or cytokine regulation in the ovaries in vivo. Indeed, the proinflammatory cytokine interleukin-1beta (IL-1beta) stimulated expression of EP2 and EP4 transcripts in concentration- and time-dependent manner in the GL cells. Furthermore, the transcript for EP2 receptor was localized in the corpus luteum of the mouse ovary by in situ hybridization, and EP2 protein was expressed in human corpus luteum as detected by immunohistochemistry.
Narko K, et al 2001 reported regulated expression of prostaglandin E-2 receptors EP2 and EP4
in human ovarian granulosa-luteal cells.
Transcripts for PGE, receptor
subtypes EP2 and EP4 are expressed in freshly isolated human granulosa
cells
and in mouse ovaries as detected by Northern blot analysis. However, EP2
and
EP4 receptor mRNA levels were low or nondetectable in cultured human granulosa-luteal (GL)
cells
suggesting that these transcripts may be under hormonal and/or cytokine
regulation in the ovaries in vivo. Indeed, the proinflammatory cytokine
interleukin-1 beta (IL-1 beta) stimulated expression of EP2 and EP4
transcripts in concentration- and time-dependent manner in the GL cells.
Furthermore, the transcript for EP2 receptor was localized in the corpus
luteum of the mouse ovary by in situ hybridization, and EP2 protein was
expressed in human corpus luteum as detected by immunohistochemistry. Our
data
suggest that IL-1 beta induces expression of EP2 and EP4 receptors in human
GL
cells, and that EP2 receptor is expressed in both human and murine luteal
glands.
Ovarian localization
Granulosa, Luteal cells
Comment
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: embryonic lethal Comment:Segi et al. (1998) generated mice deficient in the prostaglandin receptor EP4 by targeted disruption. Loss of the
EP4 receptor was not lethal in utero, but most EP4 -/- neonates became pale and lethargic approximately 24 hours
after birth and died within 72 hours. Less than 5% of the EP4 -/- mice survived and grew normally for more than 1
year.