IP ₃-Dependent Ca ²⁺ Oscillations Switch into a Dual Oscillator Mechanism in the Presence of PLC-Linked Hormones

Abstract

IP₃-dependent Ca²⁺ oscillations have been described in different cell types and ascribed to either biphasic Ca²⁺ regulation of the IP₃ receptor (IP₃R), or requiring feedback mechanisms controlling IP₃ levels. 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 integrate Ca²⁺-induced Ca²⁺ release at the IP(sub>3R, and feedback mechanisms of cross-coupling between Ca²⁺ and IP₃ reproduces this behavior. Thus, multiple Ca²⁺ oscillation models can functionally coexist in the same cell, and hormonal stimulation can switch from the simpler to the more complex to yield robust signaling.

Keywords: Ca2+ oscillations, IP3, IP3 receptor, Ca2+ signaling, mathematical modeling, hepatocyte