Irregular Ca2+ Oscillations Regulate Agonist-stimulated Transcription Through Cumulated Ca2+ Spike Duration And Ca2+ Spike Amplitude

Calcium oscillation is a universal pattern of calcium signal which is can be observed in almost all nonexciting cells. The mechanism of frequency-dependent regulation has been accepted broadly, including regulation of transcription activity, proliferation, differentiation, migration and so on. Dolmetsch has demonstrated successfully that regulation of transcriptional factor activity dependent on calcium oscillation frequency and that frequency can increase the specificity and efficiency of calcium signal. Calcium oscillation can also regulate NFκB transcriptional activity cooperate with H2O2. The study of phosphorylation and dephosphorylation of NFAT has explained how calcium oscillation could regulate transcriptional factor activity. However, what is the nature of the mechanism underlies the frequency-dependent regulation? Researcher has made deeply investigation and demonstrated that cumulated spike duration underlies the frequency-dependent regulation. Cumulated spike duration is the cumulated time that Ca2+ concentration is at certain level. During the same time duration, the higher is the frequency, the longer is the cumulated spike duration, and the lower is the frequency, the shorter is the cumulated spike duration. Thus the nature of the frequency-dependent regulation of the transcriptional factors is the cumulated spike duration-dependent mechanism. We have had profound understanding of how parameters of the calcium oscillation regulate down stream biological events through constant investigation. However, there is rising the new problem, the studies of the calcium oscillation in the past were mainly based on artificial calcium oscillation models, which were regular calcium oscillation models. Yet calcium oscillations stimulated by stimulus in most phathphysiology conditions are irregular pattern:Heterogeneity arises in the amplitude, frequency and spike duration. Hypoxia-reoxygenation can induce irregular calcium oscillations in endothelial cell, and so does the histamine in physiological concentration. However, whether the conclusion based on regular calcium oscillation model fits well with the irregular ones? So we established irregular calcium oscillation models applying calcium clamp technique that display same average amplitude and frequency but different cumulated spike duration, or same average amplitude and cumulated spike duration but different frequency, and transcriptional activities of NFκB,STAT3 and expression of IL-8,VEGF were detected based on these models. We found that transcriptional activities of NFκB,STAT3 and expression of IL-8,VEGF were same when cumulated spike duration were same, and transcriptional activities of NFκB,STAT3 and expression of IL-8,VEGF were different when cumulated spike duration were different. We also further investigated the nature of the cumulated spike duration-dependent regulation. Moreover, we also verified mechanism of cumulated spike duration-regulation in single cell level stimulated by 10μM histamine.