Gαq/11 and Gαs Play Important and Distinct Roles in Gonadotrope Cells In Vivo
Presentation Number: SUN 466
Date of Presentation: April 2nd, 2017
Chirine Toufaily*1, Han Kyeol Kim2, Rona S. Carroll3, Ulrich Boehm4, Min Chen5, Lee S. Weinstein5, Stefan Offermanns6, Daniel J. Bernard1 and Ursula B Kaiser7
1McGill University, Montreal, QC, Canada, 2Brigham and Women's Hospital, Boston, MA, 3Brigham and Women's Hospital/Harvard Med School, Boston, MA, 4University of Saarland School of Medicine, 66421 Homburg, Germany, 5NIDDK, NIH, Bethesda, MD, 6Max-Planck-Institut für Herz- und Lungenforschung, Bad Nauheim, Bad Nauheim, Germany, 7Brigham and Women's Hospital/Harvard Medical School, Boston, MA
GnRH acts via the GnRH receptor (GnRHR) to regulate LH and FSH biosynthesis and secretion by pituitary gonadotrope cells. Classically, the GnRHR was thought to signal uniquely via the G proteins, Gαq and Gα11 (Gq/11), to activate a PLC-DAG-PKC-MAPK cascade to regulate gonadotropin synthesis. Consistent with this model, ablation of extracellular-regulated kinases 1 and 2 in gonadotropes results in LH deficiency and female infertility in mice. However, FSH synthesis and regulation appeared to be relatively intact in this mouse model. Furthermore, it is now clear thatGnRHR can couple to additional Gα proteins, most notably Gαs (Gs). According to one study,GnRH regulatedLhb gene expression via both Gq/11 and Gs signaling pathways in the gonadotrope-derived LβT2 cell line. In contrast, GnRHsignaled viaGq/11 to stimulate Fshb and via Gsto both stimulate Lhb and suppressFshbin a separate study using the same cell line.To begin to understand the relative roles of different G proteins in gonadotropin production in vivo, we generated mice lacking Gq/11 or Gs specifically in gonadotropes using a Cre-lox approach. To produce Gq/11 conditional knockouts (cKOs), we crossed Gnaqfl/fl;Gna11-/- with GRIC mice, which express Cre recombinase from the endogenous Gnrhr locus. Both male and female Gq/11 cKOs failed to go through pubertal maturation, as assessed by measures of preputial separation and first estrus, respectively. We similarly produced gonadotrope-specific Gs cKO mice by crossing Gnasfl/fl and GRIC mice. Gs cKO females appeared to go through puberty normally, as assessed by examining the day of vaginal opening, and were fertile in adulthood, producing normal sized litters at normal frequencies. Adult Gs cKO males exhibited significant reductions in testis mass and pituitary expression of the FSH subunit genes (Fshb and Cga) as well as of Gnrhr relative to controls. In contrast, these males did not show differences in Lhbexpression or in circulating levels of FSH or LH. Though preliminary, these data suggest that Gs may play a greater role in FSH than in LH synthesis and that both gonadotropins may depend on intact Gq/11-dependent signaling. As these G proteins mediate the actions of multiple ligands, the relative contributions to the observed phenotypes of altered signaling by the GnRHR relative to other GPCRs in gonadotropes remain to be determined.
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