IP(3)-Dependent Ca(2+) 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.