Gβγ signaling reduces intracellular cAMP to promote meiotic progression in mouse oocytes

Abstract

In nearly every vertebrate species, elevated intracellular cAMP maintains oocytes in prophase I of meiosis. Prior to ovulation, gonadotropins trigger various intra-ovarian processes, including the breakdown of gap junctions, the activation of EGF receptors, and the secretion of steroids. These events in turn decrease intracellular cAMP levels in select oocytes to allow meiotic progression, or maturation, to resume. Studies suggest that cAMP levels are kept elevated in resting oocytes by constitutive G protein signaling, and that the drop in intracellular cAMP that accompanies maturation is due to attenuation of this inhibitory G protein-mediated signaling. Interestingly, one of these G protein regulators of meiotic arrest is the Gα s protein, which stimulates adenylyl cyclase to raise intracellular cAMP in two important animal models of oocyte development: Xenopus leavis frogs and mice. In addition to Gα s , constitutive Gβ γ activity similarly stimulates adenylyl cyclase to raise cAMP and prevent maturation in Xenopus oocytes; however, the role of Gβ γ in regulating meiosis in mouse oocytes has not been examined. Here we show that Gβγ does not contribute to the maintenance of murine oocyte meiotic arrest. In fact, contrary to observations in frog oocytes, Gβγ signaling in mouse oocytes reduces cAMP and promotes oocyte maturation, suggesting that Gβγ might in fact play a positive role in promoting oocyte maturation. These observations emphasize that, while many general concepts and components of meiotic regulation are conserved from frogs to mice, specific differences exist that may lead to important insights regarding ovarian development in vertebrates.

Oocyte Maturation A story of arrest and release

“…This study further hypothesized that LH may activate PDEs by lowering cGMP or by phosphorylating PDEs in the oocyte thereby decreasing cAMP levels (100). A more recent study, also in mouse oocyte, has reported that unlike Xenopus, the G-signaling decreases cAMP levels and can induce meiosis (158). The G-induced decrease in cAMP levels does not involve a constitutive G-signaling but rather is mediated by partially inhibiting the Gs-stimulated rise in cAMP levels.…”

The Xenopus laevis Isoform of G Protein-Coupled Receptor 3 (GPR3) Is a Constitutively Active Cell Surface Receptor that Participates in Maintaining Meiotic Arrest in X. laevis Oocytes

“…As mentioned, an unusual feature of Xenopus oocytes is that G␤␥ and G␣ s appear to signal together to stimulate adenylyl cyclase, elevate intracellular cAMP, and hold oocytes in meiotic arrest (4,(6)(7)(8). This differs from mouse oocytes, in which G␤␥ signaling may, in fact, inhibit adenylyl cyclase and promote oocyte maturation (20). The difference between these species is likely due to the presence of adenylyl cyclase VII in Xenopus (7, 21), but not mouse, oocytes.…”

Overlapping nongenomic and genomic actions of thyroid hormone and steroids

“…Second, the AR interacts with caveolin 1 and is localized primarily in lipid rafts within the membrane [74]. Third, androgen activation mediates rapid G protein signaling via the membrane-localized AR [75][76][77][78]. Finally, androgen activation of membrane-localized AR leads to rapid transactivation of the EGF receptor via a MMP-mediated release of EGF receptor ligands, after which both Akt and MAPK pathways are activated, the latter of which is important for subsequent nuclear AR-mediated signaling [79][80][81][82][83] (Fig.…”