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

Ca 2+ oscillations that depend on inositol-1,4,5-trisphosphate (IP 3 ) have been ascribed to biphasic Ca 2+ regulation of the IP 3 receptor (IP 3 R) or feedback mechanisms controlling IP 3 levels in different cell types. IP 3 uncaging in hepatocytes elicits Ca 2+ 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 Ca 2+ oscillations elicited by vasopressin. Addition of hormone to cells activated by IP 3 uncaging initiates a qualitative transition from high-frequency spatially disorganized Ca 2+ transients, to low-frequency, oscillatory Ca 2+ waves that propagate throughout the cell. A mathematical model with dual coupled oscillators that integrates Ca 2+ -induced Ca 2+ release at the IP 3 R and mutual feedback mechanisms of cross-coupling between Ca 2+ and IP 3 reproduces this behavior. Thus, multiple Ca 2+ oscillation modes can coexist in the same cell, and hormonal stimulation can switch from the simpler to the more complex to yield robust signaling.