title: Ovulation involves the luteinizing hormone-dependent activation of G(q/11) in granulosa cells.
abstract: The LH receptor (LHR) activates several families of heterotrimeric G proteins, but only the activation of Gs and subsequent generation of cAMP are universally accepted as important mediators of LH actions. To examine the involvement of the Gq/11 family on the actions of LH, we crossed Cyp19Cre and Gαq(f/f);Gα11(-/-) mice to generate mice with a granulosa cell-specific deletion of Gαq in the context of a global deletion of Gα11. Granulosa cells from Gαq(f/f);Gα11(-/-);Cre(+) mice have barely detectable levels of Gαq/11, have a normal complement of LHR, and respond to LHR activation with a transient increase in cAMP accumulation, but they fail to respond with increased inositol phosphate accumulation, an index of the activation of Gαq/11. The LHR-provoked resumption of meiosis, cumulus expansion, and luteinization are normal. However, the Gαq(f/f);Gα11(-/-);Cre(+) mice display severe subfertility because many of the oocytes destined for ovulation become entrapped in preovulatory follicles or corpora lutea. Because follicular rupture is known to be dependent on the expression of the progesterone receptor (Pgr), we examined the LHR-induced expression of Pgr and 4 of its target genes (Adamts-1, Ctsl1, Edn2, and Prkg2). These actions of the LHR were impaired in the ovaries of the Gαq(f/f);Gα11(-/-);Cre(+) mice. We conclude that the defect in follicular rupture is secondary to the failure of the LHR to fully induce the expression of the Pgr. This is the first conclusive evidence for the physiological importance of the activation of Gq/11 by the LHR and for the involvement of Gαq/11 in ovulation.
authors.affiliation: Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Breen
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Andric
authors.forename: Tai
authors.initials: T
authors.lastname: Ping
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermans
authors.forename: Jan A
authors.initials: JA
authors.lastname: Gossen
authors.forename: Mario
authors.initials: M
authors.lastname: Ascoli
mesh_terms: D000818:Animals; D054885:Cumulus Cells / Q000166:cytology / Q000378:metabolism; D010064:Embryo Implantation / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics; D005306:Fertilization / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007986:Luteinizing Hormone / Q000378:metabolism*; D008540:Meiosis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010060:Ovulation / Q000235:genetics / Q000502:physiology*; D011974:Receptors, LH / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
chemical_list: D011974:Receptors, LH; D011980:Receptors, Progesterone; D007986:Luteinizing Hormone; D043802:GTP-Binding Protein alpha Subunits, Gq-G11