Abstract
Many cellular stimuli induce oscillations of cytosolic calcium concentration ([Ca2+]). Ca2+ signals are generated by a cascade involving agonist binding to G protein-coupled receptor (GPCR), generation of inositol 1,4,5-trisphosphate (IP3), release of Ca2+ from endoplasmic reticulum through IP3 receptor (IP3R).In the previous study, we have developed Forster resonance energy transfer based IP3 sensors and monitored the IP3 dynamics during Ca2+ oscillations. In stimulated HeLa cells, IP3 started to increase at a relatively constant rate before the pacemaker Ca2+ rise, and IP3 gradually accumulated in the cytosol with a little fluctuations during cytosolic Ca2+ oscillations. In this study, we compared the relationship between IP3 concentration ([IP3]) and the frequency of Ca2+ oscillations, and found they are well correlated but the relationships are different among the types of stimulated GPCRs. This result shows the frequency of Ca2+ oscillations are not only determined by [IP3]. To explain the result, we developed a kinetic model that reproduces Ca2+ and IP3 dynamics observed in HeLa cells by constructing a novel 6-state IP3R model. We found that Ca2+-dependent regulation of IP3-binding affinity of IP3R and the feedback regulation of phospholipase C, which produces IP3 from phosphatidylinositol 4,5-bisphosphate, by cytosolic Ca2+ are essential ingredients in the model.
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