Research ArticleFertility

The prostaglandin transporter (PGT) as a potential mediator of ovulation

Science Translational Medicine  11 May 2016:
Vol. 8, Issue 338, pp. 338ra68
DOI: 10.1126/scitranslmed.aad2709

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Prostaglandins are known to play an important role in ovulation, but the role of prostaglandin transporter, a protein that transports prostaglandins across the cell membrane, was not well understood. By studying the process of ovulation in human cells and in mouse models, Yerushalmi et al. found that the activity of the prostaglandin transporter regulates the extracellular concentration of prostaglandin E2 in the ovarian follicles and thereby determines whether ovulation will occur. The authors also showed that inhibiting this transporter blocks ovulation in mice, suggesting that this approach may be a feasible method of contraception if these results are confirmed in humans.

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.

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