Modeling Ca2+ signaling differentiation during oocyte maturation

Ca²⁺ is a fundamental intracellular signal that mediates a variety of disparate physiological functions often in the same cell. Ca²⁺ signals span a wide range of spatial and temporal scales, which endow them with the specificity required to induce defined cellular functions. Furthermore, Ca²⁺ signaling is highly plastic as it is modulated dynamically during normal physiological development and under pathological conditions. However, the molecular mechanisms underlying Ca²⁺ signaling differentiation during cellular development remain poorly understood. Oocyte maturation in preparation for fertilization provides an exceptionally well-suited model to elucidate Ca²⁺ signaling regulation during cellular development. This is because a Ca²⁺ signal with specialized spatial and temporal dynamics is universally essential for egg activation at fertilization. Here we use mathematical modeling to define the critical determinants of Ca²⁺ signaling differentiation during oocyte maturation. We show that increasing IP₃ receptor (IP₃R) affinity replicates both elementary and global Ca²⁺ dynamics observed experimentally following oocyte maturation. Furthermore, our model reveals that because of the Ca²⁺ dependency of both SERCA and the IP₃R, increased IP₃R affinity shifts the system's equilibrium to a new steady state of high cytosolic Ca²⁺, which is essential for fertilization. Therefore our model provides unique insights into how relatively small alterations of the basic molecular mechanisms of Ca²⁺ signaling components can lead to dramatic alterations in the spatio-temporal properties of Ca²⁺ dynamics.