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Role of Mitogen-Activated Protein Kinase in Prostaglandin F₂ Action in Human Granulosa-Luteal Cells¹

Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5; and Taipei Medical College Hospital (C.-R.T.), 110 Taipei, Taiwan

Address all correspondence and requests for reprints to: Dr. Peter C. K. Leung, Department of Obstetrics and Gynecology, University of British Columbia, Room 2H30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5. E-.mail: peleung@interchange.ubc.ca.

In the ovary it has been demonstrated that PGF₂ activates the phospholipase C (PLC)/diacylglycerol/protein kinase C pathway. However, little is known about the downstream signaling events that mediate subsequent cellular responses such as steroidogenesis. The present study was designed to examine the effect of PGF₂ on activation of the mitogen-activated protein kinase (MAPK) signaling pathway and its physiological role in human granulosa-luteal cells (hGLCs). Human GLCs, obtained from women undergoing in vitro fertilization-embryo transfer, were treated with increasing concentrations of PGF₂ (10 nmol/L to 10 µmol/L) for 5 min. For time-course experiments, hGLCs were treated with 1 µmol/L PGF₂ for 1, 5, 10, or 20 min. Western blot analysis, using a monoclonal antibody that detected the phosphorylated forms of extracellular signal-regulated kinases 1 and 2 (p42^mapk and p44^mapk, respectively), demonstrated that PGF₂ activated MAPK in hGLCs in a dose- and time-dependent manner. Treatment of the cells with neomycin (10 mmol/L; a PLC inhibitor), bisindolylmaleimide I (5 µmol/L; a PKC inhibitor), or PD98059 (50 µmol/L; a MEK inhibitor and a MAPK kinase inhibitor) significantly attenuated the PGF₂-induced activation of MAPK. In contrast, MAPK activation was not significantly affected by pertussis toxin (200 ng/mL; a G_i inhibitor) pretreatment. To determine the role of MAPK in steroidogenesis, hGLCs were treated with PGF₂ (1 µmol/L), hCG (1 IU/mL), or PGF₂ plus hCG in the presence or absence of PD98059. Progesterone levels in the culture medium were examined by RIA. Treatment of hGLCs with PGF₂ significantly inhibited hCG-induced progesterone production. The presence of the MEK inhibitor, PD98059, reversed the inhibitory effect of PGF₂ on hCG-induced progesterone production. To our knowledge, it is the first demonstration of PGF₂-induced activation of the MAPK signaling pathway in the human ovary. These results indicated that PGF₂ activated MAPK subsequent to PLC and PKC activation through pertussis toxin-insensitive G protein in hGLCs. Further, we demonstrated that PGF₂-induced MAPK activation is associated with modulation of progesterone production. These results support the idea that the MAPK signaling pathway is involved in mediating PGF₂ actions in the human ovary.

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