Abstract
Many studies have shown that cyclic adenosine-5′-monophosphate (cAMP)-dependent protein kinase A (PKA) and G-protein-coupled receptor 3 (GPR3) are crucial for controlling meiotic arrest in oocytes. However, it is unclear how gonadotropins modulate these factors to regulate oocyte maturation, especially by gap junctional communication (GJC). Using an in vitro meiosis-arrested mouse cumulus-oocyte complex (COC) culture model, we showed that there is a close relationship between follicle-stimulating hormone (FSH) and the PKA type I (PKAI) and GPR3. The effect of FSH on oocyte maturation was biphasic, initially inhibitory and then stimulatory. During FSH-induced maturation, rapid cAMP surges were observed in both cumulus cells and oocyte. Most GJC between cumulus cells and oocyte ceased immediately after FSH stimulation and recommenced after the cAMP surge. FSH-induced maturation was blocked by PKAI activator 8-AHA-cAMP. Levels of PKAI regulatory subunits and GPR3 decreased and increased, respectively, after FSH stimulation. In the presence of the GJC inhibitor carbenoxolone (CBX), FSH failed to induce the meiotic resumption and the changes in PKAI, GPR3 and cAMP surge in oocyte were no longer detected. Furthermore, GPR3 was upregulated by high cAMP levels, but not by PKAI activation. When applied after FSH stimulation, the specific phosphodiesterase 3A (PDE3A) inhibitor cilostamide immediately blocked meiotic induction, regardless of when it was administered. PKAI activation inhibited mitogen-activated protein kinase (MAPK) phosphorylation in the oocytes of COCs, which participated in the initiation of FSH-induced meiotic maturation in vitro. Just before FSH-induced meiotic maturation, cAMP, PKAI, and GPR3 returned to basal levels, and PDE3A activity and MAPK phosphorylation increased markedly. These experiments show that FSH induces a transient increase in cAMP levels and regulates GJC to control PKAI and GPR3 activities, thereby creating an inhibitory phase. After PDE3A and MAPK activities increase, meiosis resumes.
Highlights
Even if fully grown oocytes in follicles acquire complete maturation potential, they remain at the germinal vesicle (GV) stage before the gonadotropin surge
To determine why follicle-stimulating hormone (FSH) initially inhibited oocyte maturation, mouse cumulus-oocyte complex (COC) were cultured in control HX medium or HX medium supplemented with 50 IU/L FSH
We found that FSH controls oocyte maturation through the gap junctional communication (GJC)-dependent modulation of the activities of PKA type I (PKAI) and G-protein-coupled receptor 3 (GPR3) in mouse COCs, and that the activities of mitogenactivated protein kinase (MAPK) and phosphodiesterase 3A (PDE3A) are arrested until just before the resumption of meiosis
Summary
Even if fully grown oocytes in follicles acquire complete maturation potential, they remain at the germinal vesicle (GV) stage before the gonadotropin surge. Elevated levels of cAMP in the oocyte maintain meiotic arrest by activating protein kinase A (PKA). CAMP in oocyte is supplied by follicle cells, through gap junctional communication (GJC), and by oocyte itself. They are all necessary for meiotic arrest. The mouse oocyte generates cAMP through the G-protein-coupled receptor 3 (GPR3) [8,9,10,11]; the Gs G-protein [12], and AC [13] If any of these components is inhibited or removed from the oocyte, germinal vesicle breakdown (GVBD) proceeds spontaneously. NPPC increases cGMP levels in cumulus cells and oocytes, and inhibits the resumption of meiosis in vitro [15]
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