title: The prostaglandin transporter (PGT) as a potential mediator of ovulation.
abstract: Prostaglandins (PGs) play an important role in the ovulatory process. However, the role of the PG transporter (PGT) in this context remains unknown. We report that the expression of PGT, a transmembrane PG carrier protein, is markedly up-regulated in preovulatory human granulosa cells (GCs). Treatment with human chorionic gonadotropin (hCG), an ovulatory trigger, significantly increases the expression of PGT mRNA and protein in human GCs both in vivo and in vitro. The hCG-induced increase in the expression of PGT in cultured human GCs is mediated via protein kinase A and protein kinase C by way of the extracellular signal-regulated kinase pathway. PGT in cultured human GCs mediates the uptake of PGE2, thereby regulating its extracellular concentration. In vivo treatment of mice with PGT inhibitors effectively blocks ovulation and markedly attenuates the expression of key ovulatory genes. We hypothesize that the inhibition of PGT activity in GCs increases the extracellular concentration of PGE2, the ability of which to exert its ovulatory effect is compromised by desensitization of its cognate receptors. Together, these findings support the idea that PGT is an important mediator of ovulation and that its inhibitors may be viewed as potential candidates for nonhormonal contraception. These findings may also fill the gap in the understanding of PGT signaling, enhance the understanding of ovulatory disorders, and facilitate the treatment of infertility or subfertility in women by using nonsteroidal PG-based therapeutic approaches.
authors.affiliation: IVF Unit and Reproduction Laboratory, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer 5262100, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Gil M
authors.initials: GM
authors.lastname: Yerushalmi
authors.affiliation: IVF Unit and Reproduction Laboratory, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer 5262100, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Markman
authors.affiliation: IVF Unit and Reproduction Laboratory, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer 5262100, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Yung
authors.affiliation: IVF Unit and Reproduction Laboratory, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer 5262100, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Ettie
authors.initials: E
authors.lastname: Maman
authors.affiliation: Department of Pathology, Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Tel Hashomer, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Sarit
authors.initials: S
authors.lastname: Aviel-Ronen
authors.affiliation: IVF Unit and Reproduction Laboratory, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer 5262100, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Raoul
authors.initials: R
authors.lastname: Orvieto
authors.affiliation: Department of Obstetrics and Gynecology, Warren Alpert Medical School, Brown University, Providence, RI 02906, USA.
authors.forename: Eli Y
authors.initials: EY
authors.lastname: Adashi
authors.affiliation: IVF Unit and Reproduction Laboratory, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer 5262100, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Hourvitz
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism; D010060:Ovulation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D006063:Chorionic Gonadotropin; D027361:Organic Anion Transporters; C503526:SLCO2A1 protein, human; D015232:Dinoprostone