Calcium signaling in oocyte quality and functionality and its application

Abstract

Calcium (Ca²⁺) is a second messenger for many signal pathways, and changes in intracellular Ca²⁺ concentration ([Ca²⁺]i) are an important signaling mechanism in the oocyte maturation, activation, fertilization, function regulation of granulosa and cumulus cells and offspring development. Ca²⁺ oscillations occur during oocyte maturation and fertilization, which are maintained by Ca²⁺ stores and extracellular Ca²⁺ ([Ca²⁺]e). Abnormalities in Ca²⁺ signaling can affect the release of the first polar body, the first meiotic division, and chromosome and spindle morphology. Well-studied aspects of Ca²⁺ signaling in the oocyte are oocyte activation and fertilization. Oocyte activation, driven by sperm-specific phospholipase PLCζ, is initiated by concerted intracellular patterns of Ca²⁺ release, termed Ca²⁺ oscillations. Ca²⁺ oscillations persist for a long time during fertilization and are coordinately engaged by a variety of Ca²⁺ channels, pumps, regulatory proteins and their partners. Calcium signaling also regulates granulosa and cumulus cells' function, which further affects oocyte maturation and fertilization outcome. Clinically, there are several physical and chemical options for treating fertilization failure through oocyte activation. Additionally, various exogenous compounds or drugs can cause ovarian dysfunction and female infertility by inducing abnormal Ca²⁺ signaling or Ca²⁺ dyshomeostasis in oocytes and granulosa cells. Therefore, the reproductive health risks caused by adverse stresses should arouse our attention. This review will systematically summarize the latest research progress on the aforementioned aspects and propose further research directions on calcium signaling in female reproduction.

Keywords: Ca2+ oscillations; calcium; female fertility; fertilization; oocyte activation; oocyte maturation.

Figure 1

Signaling pathways involved in oocyte fertilization of mammals. Sperm factor PLCζ acts on PIP2 in intracellular vesicles to generate IP3, which stimulates IP3R-mediated Ca²⁺ release from ER Ca²⁺ store. Once the ER store is emptied, the egg replenishes the depleted ER store by influx of extracellular Ca²⁺, which was known as store-operated Ca²⁺ entry (SOCE). The main molecular mediators of SOCE are STIM proteins and ORAI proteins. In response to a reduction in ER Ca²⁺, the STIM proteins interact directly with ORAI channels, inducing Ca²⁺ influx. This Ca²⁺ is subsequently pumped back into the ER by the action of sarco-ER Ca²⁺ ATPases (SERCA). Meanwhile, to avoid cytotoxicity from excessive intracellular Ca²⁺ in oocytes, plasma membrane Ca²⁺ ATPase (PMCA) pumps transport some of the Ca²⁺ out of the cytoplasm. When the excess Ca²⁺ in the cytoplasm are excreted, the egg needs to take in some Ca²⁺ to balance the intracellular ion level, and this process is mainly achieved through voltage-gated Ca²⁺ channels, CaV3.2, and transient receptor potential channels, TRPV3 and TRPM7.

Figure 2

Sperm factor PLCζ acts on PIP2 in intracellular vesicles to generate IP3, which stimulates IP3R-mediated Ca²⁺ release from ER Ca²⁺ store. Ca²⁺ oscillations activate the Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), leading to WEE1B activation. The activate WEE1B phosphorylates CDK1 and inhibits MPF activity. In addition, CaMKII activation results in EMI2 phosphorylation, and phosphorylated EMI2 loses its ability to inhibit the anaphase promoting complex or cyclosome (APC/C). As a result, APC/C disrupts EMI2 and cyclin B, leading to a loss of MPF activity. The destabilized MPF triggers an exit from M-II arrest. Protein kinase C (PKC) binds to synthetic DAGs, which acts on myristoylated alanine-rich C kinase substrate (MARCKS), resulting in reorganization of cortical actin filaments and cortical granule exocytosis. The pronucleus formation of the oocyte also depends on a decrease in MAPK activity. In mouse fertilized eggs, MAPK activity begins to decline when Ca²⁺ oscillations last for 2 hours and gradually declines for several hours after pronuclear formation.