Zn²⁺ is Essential for Ca²⁺ Oscillations in Mouse Eggs

Changes in the intracellular concentration of free calcium (Ca²⁺) underpin egg activation and initiation of development in animals and plants. In mammals, the Ca²⁺ release is periodical, known as Ca²⁺ oscillations, and mediated by the type 1 inositol 1,4,5-trisphosphate receptor (IP₃R1). Another divalent cation, zinc (Zn²⁺), increases exponentially during oocyte maturation and is vital for meiotic transitions, arrests, and polyspermy prevention. It is unknown if these pivotal cations interplay during fertilization. Here, using mouse eggs, we showed that basal concentrations of labile Zn²⁺ are indispensable for sperm-initiated Ca²⁺ oscillations because Zn²⁺-deficient conditions induced by cell-permeable chelators abrogated Ca²⁺ responses evoked by fertilization and other physiological and pharmacological agonists. We also found that chemically- or genetically generated eggs with lower levels of labile Zn²⁺ displayed reduced IP₃R1 sensitivity and diminished ER Ca²⁺ leak despite the stable content of the stores and IP₃R1 mass. Resupplying Zn²⁺ restarted Ca²⁺ oscillations, but excessive Zn²⁺ prevented and terminated them, hindering IP₃R1 responsiveness. The findings suggest that a window of Zn²⁺ concentrations is required for Ca²⁺ responses and IP₃R1 function in eggs, ensuring optimal response to fertilization and egg activation.