G Protein and Androgen Signaling in Ovarian Function
Deng, James Yang
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Oocytes are held in meiotic arrest in prophase I until ovulation when gonadotropins trigger a subpopulation of oocytes to resume meiosis in a process termed "maturation." Meiotic arrest is maintained through a mechanism whereby constitutive cAMP production exceeds phosphodiesterase-mediated degradation, leading to elevated intracellular cAMP. Studies have implicated a constitutively activated Gas-coupled receptor, G protein-coupled receptor 3 (GPR3), as one of the molecules responsible for maintaining meiotic arrest in mouse oocytes. Here, we characterized the signaling and functional properties of GPR3 by using the more amenable model system of Xenopus laevis oocytes. We cloned the Xenopus laevis isoform of GPR3 (XGPR3) from oocytes and showed that overexpressed XGPR3 elevated intra-oocyte cAMP, in large part due to Gbg signaling. Overexpressed XGPR3 suppressed steroid-triggered kinase activation and maturation of isolated oocytes, as well as gonadotropin-induced maturation of follicle-enclosed oocytes. In contrast, depletion of XGPR3 using antisense oligodeoxynucleotides enhanced steroid- and gonadotropin-mediated oocyte maturation. Interestingly, collagenase treatment of Xenopus oocytes cleaved and inactivated cell surface XGPR3, which enhanced steroid-triggered oocyte maturation and activation of MAPK. In addition, hCG treatment of follicle-enclosed oocytes triggered matrix metalloproteinase-mediated cleavage of XGPR3 at the oocyte cell surface. Collectively, these results suggest that GPR3 moderates the oocyte response to maturation-promoting signals, and that gonadotropin-mediated activation of metalloproteinases may sensitize oocytes for maturation by inactivating constitutive GPR3 signaling.