IP₃-Dependent Ca²⁺ Oscillations Switch into a Dual Oscillator Mechanism in the Presence of PLC-Linked Hormones.

Abstract

Ca²⁺ oscillations that depend on inositol-1,4,5-trisphosphate (IP₃) have been ascribed to biphasic Ca²⁺ regulation of the IP₃ receptor (IP₃R) or feedback mechanisms controlling IP₃ levels in different cell types. IP₃ uncaging in hepatocytes elicits Ca²⁺ transients that are often localized at the subcellular level and increase in magnitude with stimulus strength. However, this does not reproduce the broad baseline-separated global Ca²⁺ oscillations elicited by vasopressin. Addition of hormone to cells activated by IP₃ uncaging initiates a qualitative transition from high-frequency spatially disorganized Ca²⁺ transients, to low-frequency, oscillatory Ca²⁺ waves that propagate throughout the cell. A mathematical model with dual coupled oscillators that integrates Ca²⁺-induced Ca²⁺ release at the IP₃R and mutual feedback mechanisms of cross-coupling between Ca²⁺ and IP₃ reproduces this behavior. Thus, multiple Ca²⁺ oscillation modes can coexist in the same cell, and hormonal stimulation can switch from the simpler to the more complex to yield robust signaling.