Figure 7. Schematic of proposed regulation of IP3R1 function by Zn²⁺ in eggs and fertilized zygotes.

In MII eggs, left panel, IP₃R1s are in a Ca²⁺-release permissive state with optimal levels of cytoplasmic Ca²⁺ and Zn²⁺ and maximum ER content, but Ca²⁺ is maintained at resting levels by the combined actions of pumps, ER Ca²⁺ leak, and reduced influx. Once fertilization takes place, left center panel, robust IP₃ production induced by the sperm-borne PLCζ leads to Ca²⁺ release through ligand-induced gating of IP₃R1. Continuous IP₃ production and refilling of the stores via Ca²⁺ influx ensure the persistence of the oscillations. Zn²⁺ release occurs in association with first few Ca²⁺ rises and cortical granule exocytosis, Zn²⁺ sparks, lowering Zn²⁺ levels but not sufficiently to inhibit IP₃R1 function. Zn²⁺ deficiency caused by TPEN or other permeable Zn²⁺ chelators, right center panel, dose-dependently impairs IP₃R1 function and limits Ca²⁺ release. We propose this is accomplished by stripping the Zn²⁺ bound to the residues of the zinc-finger motif in the LNK domain of IP₃R1 that prevents the allosteric modulation of the gating process induced by IP₃ or other agonists. We propose that excess Zn²⁺, right panel, also inhibits IP₃R1-mediate Ca²⁺ release, possibly by non-specific binding of thiol groups present in cysteine residues throughout the receptor (denoted by a ?). We submit that optimal Ca²⁺ oscillations in mouse eggs unfold in the presence of a permissive range of Zn²⁺ concentration.