We present a novel nonlinear state transition model for inositol 1, 4, 5-trisphosphate receptors (IP₃Rs) that incorporates a pre-activated state, as suggested by electron microscopy observations. Our model provides a theoretical framework for the biphasic Ca^2+ dependence of IP₃Rs and accurately reproduces their experimentally observed state distribution under saturating IP₃ conditions. By integrating receptor dynamics with cytoplasmic and endoplasmic reticulum (ER) calcium exchange, we simulate IP₃R-mediated Ca^2+ oscillations governed by six key conformational states. A pivotal finding is that IP₃ regulates these oscillations in a switch-like manner: once a critical IP₃ concentration is reached, the system abruptly transitions to sustained, constant-amplitude oscillations that quickly terminate when the concentration exceeds a secondary threshold. These results underscore the crucial role of the pre-activated state in modulating calcium signaling.
Peng et al. (Mon,) studied this question.