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Dephosphorylation and inactivation of NPR2 guanylyl cyclase in granulosa cells contributes to the LH-induced decrease
Jeremy R Egbert1, Leia C Shuhaibar1, Aaron B Edmund2
1Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Abstract:
In mammals, the meiotic cell cycle of oocytes starts during embryogenesis and then pauses. Much later, in preparation for fertilization, oocytes within preovulatory follicles resume meiosis in response to luteinizing hormone (LH). Before LH stimulation, the arrest is maintained by diffusion of cyclic (c)GMP into the oocyte from the surrounding granulosa cells, where it is produced by the guanylyl cyclase natriuretic peptide receptor 2 (NPR2). LH rapidly reduces the production of cGMP, but how this occurs is unknown. Here, using rat follicles, we show that within 10 min, LH signaling causes dephosphorylation and inactivation of NPR2 through a process that requires the activity of phosphoprotein phosphatase (PPP)-family members. The rapid dephosphorylation of NPR2 is accompanied by a rapid phosphorylation of the cGMP phosphodiesterase PDE5, an enzyme whose activity is increased upon phosphorylation. Later, levels of the NPR2 agonist C-type natriuretic peptide decrease in the follicle, and these sequential events contribute to the decrease in cGMP that causes meiosis to resume in the oocyte.
Insights
Luteinizing hormone (LH) rapidly halts oocyte maturation by inactivating the cyclic GMP (cGMP) production enzyme, natriuretic peptide receptor 2 (NPR2), allowing fertilization readiness.
Area of Science:
- Reproductive Biology
- Cell Signaling
- Molecular Endocrinology
Background:
- Mammalian oocyte meiosis resumes in response to luteinizing hormone (LH) after a prolonged arrest.
- Cyclic guanosine monophosphate (cGMP) maintains meiotic arrest by diffusing from granulosa cells into the oocyte.
- cGMP is produced by guanylyl cyclase natriuretic peptide receptor 2 (NPR2) in granulosa cells.
Purpose of the Study:
- To elucidate the rapid mechanism by which LH signaling reduces cGMP levels in oocytes.
- To identify the molecular players involved in LH-induced meiotic resumption.
Main Methods:
- Experiments were conducted using rat preovulatory follicles.
- Investigated the phosphorylation status and activity of NPR2 and PDE5 following LH stimulation.
- Utilized inhibitors to probe the role of phosphoprotein phosphatase (PPP)-family members.
Main Results:
- LH signaling rapidly (within 10 minutes) induces dephosphorylation and inactivation of NPR2 via PPP-family members.
- LH stimulation also leads to rapid phosphorylation and activation of cGMP phosphodiesterase PDE5.
- Downregulation of the NPR2 agonist, C-type natriuretic peptide, occurs later in the follicle.
Conclusions:
- LH rapidly inhibits cGMP production by inactivating NPR2 and promotes cGMP degradation by activating PDE5.
- These coordinated signaling events lead to decreased oocyte cGMP levels, triggering meiotic resumption.
- This provides a molecular explanation for the rapid LH-induced meiotic progression essential for ovulation.
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