The variety of cytosolic calcium responses and possible roles of PLC and PKC

A model of ligand-induced intracellular calcium (Ca²⁺) responses incorporating phospholipase C (PLC) and protein kinase C (PKC) is developed for the purpose of understanding the mechanisms underlying the observed temporal patterns of intracellular calcium (Ca²⁺_i) under sustained agonist stimulation. Some studies have suggested that inhibition of ligand receptors and PLC by PKC could generate sinusoidal Ca²⁺ oscillations, while PKC-independent Ca²⁺-induced Ca²⁺ release (CICR) via IP₃-gated Ca²⁺ channels on the endoplasmic reticulum (ER) is believed to be responsible for baseline spiking. However, some evidence also indicates that baseline spiking can be observed under high-PKC activity, or under low-PKC activity with low agonist stimulus, as well. Insight into the basis of these observations regarding the role of PKC in Ca²⁺ _i response patterns can be gained by developing and analyzing a mathematical model of Ca²⁺_i responses. We do this herein and find that (1) interaction of CICR and the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump is enough to generate both types of Ca ²⁺_i oscillations, (2) there exist four possible Ca ²⁺_i response patterns under sustained agonist stimulus: a sub-threshold response (SR), baseline spiking, sinusoidal oscillations (SO) and transient with plateau, and (3) the IP₃ concentration, which is controlled by the strength of the interaction between PKC and PLC, can be used to predict the Ca²⁺_i response patterns. From this analysis we conclude that the different patterns of Ca²⁺_i oscillations can be understood as a generic consequence of the interactions between CICR via the IP₃-gated Ca²⁺ channels in response to changes in the level of IP₃, and re-uptake into the ER/SR via the SERCA pump. PKC, in conjunction with PLC, can act as a switch between different Ca²⁺_i response patterns by modulating the cytosolic IP₃ level, which determines the Ca²⁺_i patterns.