The role of ATP in the differential ability of Sr(2+) to trigger Ca(2+) oscillations in mouse and human eggs

At fertilization in mice and humans, the activation of the egg is caused by a series of repetitive Ca(2+) oscillations which are initiated by phospholipase-C(zeta)ζ that generates inositol-1,4,5-trisphophate (InsP(3)). Ca(2+) oscillations and egg activation can be triggered in mature mouse eggs by incubation in Sr(2+) containing medium, but this does not appear to be effective in human eggs. Here, we have investigated the reason for this apparent difference using mouse eggs, and human eggs that failed to fertilize after IVF or ICSI. Mouse eggs incubated in Ca(2+)-free, Sr(2+)-containing medium immediately underwent Ca(2+) oscillations but human eggs consistently failed to undergo Ca(2+) oscillations in the same Sr(2+) medium. We tested the InsP(3)-receptor (IP3R) sensitivity directly by photo-release of caged InsP(3) and found that mouse eggs were about 10 times more sensitive to InsP(3) than human eggs. There were no major differences in the Ca(2+) store content between mouse and human eggs. However, we found that the ATP concentration was consistently higher in mouse compared to human eggs. When ATP levels were lowered in mouse eggs by incubation in pyruvate-free medium, Sr(2+) failed to cause Ca(2+) oscillations. When pyruvate was added back to these eggs, the ATP levels increased and Ca(2+) oscillations were induced. This suggests that ATP modulates the ability of Sr(2+) to stimulate IP3R-induced Ca(2+) release in eggs. We suggest that human eggs may be unresponsive to Sr(2+) medium because they have a lower level of cytosolic ATP.