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

Abstract

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 Ca2+i oscillations, (2) there exist four possible Ca2+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.