TY - JOUR
T1 - ABCC4 is a PGE2 efflux transporter in the ovarian follicle
T2 - A mediator of ovulation and a potential non-hormonal contraceptive target
AU - Yerushalmi, Gil M.
AU - Shuraki, Batel
AU - Yung, Yuval
AU - Maman, Ettie
AU - Baum, Micha
AU - Hennebold, Jon D.
AU - Adashi, Eli Y.
AU - Hourvitz, Ariel
N1 - Publisher Copyright:
© 2023 Federation of American Societies for Experimental Biology.
PY - 2023/4
Y1 - 2023/4
N2 - The role of prostaglandins (PGs) in the ovulatory process is known. However, the role of the ATP binding cassette subfamily C member 4 (ABCC4), transmembrane PG carrier protein, in ovulation remains unknown. We report herein that ABCC4 expression is significantly upregulated in preovulatory human granulosa cells (GCs). We found that PGE2 efflux in cultured human GCs is mediated by ABCC4 thus regulating its extracellular concentration. The ABCC4 inhibitor probenecid demonstrated effective blocking of ovulation and affects key ovulatory genes in female mice in vivo. We postulate that the reduction in PGE2 efflux caused by the inhibition of ABCC4 activity in GCs decreases the extracellular concentration of PGE2 and its ovulatory effect. Treatment of female mice with low dose of probenecid as well as with the PTGS inhibitor indomethacin or Meloxicam synergistically blocks ovulation. These results support the hypothesis that ABCC4 has an important role in ovulation and might be a potential target for non-hormonal contraception, especially in combination with PGE2 synthesis inhibitors. These findings may fill the gap in understanding the role of ABCC4 in PGE2 signaling, enhance the understanding of ovulatory disorders, and facilitate the treatment and control of fertility.
AB - The role of prostaglandins (PGs) in the ovulatory process is known. However, the role of the ATP binding cassette subfamily C member 4 (ABCC4), transmembrane PG carrier protein, in ovulation remains unknown. We report herein that ABCC4 expression is significantly upregulated in preovulatory human granulosa cells (GCs). We found that PGE2 efflux in cultured human GCs is mediated by ABCC4 thus regulating its extracellular concentration. The ABCC4 inhibitor probenecid demonstrated effective blocking of ovulation and affects key ovulatory genes in female mice in vivo. We postulate that the reduction in PGE2 efflux caused by the inhibition of ABCC4 activity in GCs decreases the extracellular concentration of PGE2 and its ovulatory effect. Treatment of female mice with low dose of probenecid as well as with the PTGS inhibitor indomethacin or Meloxicam synergistically blocks ovulation. These results support the hypothesis that ABCC4 has an important role in ovulation and might be a potential target for non-hormonal contraception, especially in combination with PGE2 synthesis inhibitors. These findings may fill the gap in understanding the role of ABCC4 in PGE2 signaling, enhance the understanding of ovulatory disorders, and facilitate the treatment and control of fertility.
UR - http://www.scopus.com/inward/record.url?scp=85150671641&partnerID=8YFLogxK
U2 - 10.1096/fj.202101931RR
DO - 10.1096/fj.202101931RR
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C2 - 36943419
AN - SCOPUS:85150671641
SN - 0892-6638
VL - 37
JO - FASEB Journal
JF - FASEB Journal
IS - 4
M1 - e22858
ER -