Regulation of inositol 1,4,5-trisphosphate receptor function during mouse oocyte maturation

At the time of fertilization, an increase in the intracellular Ca ²⁺ concentration ([Ca ²⁺] _i) underlies egg activation and initiation of development in all species studied to date. The inositol 1,4,5-trisphosphate receptor (IP ₃R1), which is mostly located in the endoplasmic reticulum (ER) mediates the majority of this Ca ²⁺ release. The sensitivity of IP ₃R1, that is, its Ca ²⁺ releasing capability, is increased during oocyte maturation so that the optimum [Ca ²⁺] _i response concurs with fertilization, which in mammals occurs at metaphase of second meiosis. Multiple IP ₃R1 modifications affect its sensitivity, including phosphorylation, sub-cellular localization, and ER Ca ²⁺ concentration ([Ca ²⁺] _ER). Here, we evaluated using mouse oocytes how each of these factors affected IP ₃R1 sensitivity. The capacity for IP ₃-induced Ca ²⁺ release markedly increased at the germinal vesicle breakdown stage, although oocytes only acquire the ability to initiate fertilization-like oscillations at later stages of maturation. The increase in IP ₃R1 sensitivity was underpinned by an increase in [Ca ²⁺] _ER and receptor phosphorylation(s) but not by changes in IP ₃R1 cellular distribution, as inhibition of the former factors reduced Ca ²⁺ release, whereas inhibition of the latter had no impact. Therefore, the results suggest that the regulation of [Ca ²⁺] _ER and IP ₃R1 phosphorylation during maturation enhance IP ₃R1 sensitivity rendering oocytes competent to initiate oscillations at the expected time of fertilization. The temporal discrepancy between the initiation of changes in IP ₃R1 sensitivity and acquisition of mature oscillatory capacity suggest that other mechanisms that regulate Ca ²⁺ homeostasis also shape the pattern of oscillations in mammalian eggs.