The Phase Lag between Agonist-Induced Oscillatory Ca 2+ and IP 3 Signals Does Not Imply Causality (December 2015).

Activated phospholipase C (PLC*) generates 1,4,5-triphosphate (IP ₃ ) and diacylglycerol (DAG) from phosphatidyl inositol (PIP ₂ ). The DAG remains in the plasma membrane and co-activates conventional protein kinase C (PKC) with Ca ²⁺ . We have developed a mathematical model for the activation of the Ca ²⁺ -dependent PKC and its negative feedback on phospholipase C (PLC) and coupled it to the De Young-Keizer model for IP ₃ mediated Ca ²⁺ oscillations. The model describes the cascade of reactions for the translocation of PKC to plasma membrane, and simulates activation of Ca ²⁺ and diacylglycerol (DAG) oscillations. The model demonstrates that oscillations in Ca ²⁺ and DAG are possible with or without a positive Ca ²⁺ feedback on phospholipase C consistent with experiment. In many experimental studies, the timing of the peaks of the Ca ²⁺ and IP ₃ oscillations have been used to suggest causality, i.e. that the IP ₃ oscillations cause the Ca ²⁺ oscillations. The model is used to explore this question. To this end, the positive and negative feedback between Ca ²⁺ and IP ₃ production are modulated, resulting in changes to the phase lag between the peaks in [Ca ²⁺ ] _cyt and [IP] _cyt . The model simulates a possible experimental protocol that can be used to differentiate whether or not the positive feedback of Ca ²⁺ on PLC is needed for the oscillations.