Cumulated Ca2⁺ spike duration underlies Ca2⁺ oscillation frequency-regulated NFκB transcriptional activity.

Ca(2+) oscillations drive downstream events, like transcription, in a frequency-dependent manner. Why Ca(2+) oscillation frequency regulates transcription has not been clearly revealed. A variation in Ca(2+) oscillation frequency apparently leads to a variation in the time duration of cumulated Ca(2+) elevations or cumulated Ca(2+) spike duration. By manipulating Ca(2+) spike duration, we generated a series of Ca(2+) oscillations with the same frequency but different cumulated Ca(2+) spike durations, as well as Ca(2+) oscillations with the different frequencies but the same cumulated Ca(2+) spike duration. Molecular assays demonstrated that, when generated in 'artificial' models alone, under physiologically simulated conditions or repetitive pulses of agonist exposure, Ca(2+) oscillation regulates NFκB transcriptional activity, phosphorylation of IκBα and Ca(2+)-dependent gene expression all in a way actually dependent on cumulated Ca(2+) spike duration whether or not frequency varies. This study underlines that Ca(2+) oscillation frequency regulates NFκB transcriptional activity through cumulated Ca(2+) spike-duration-mediated IκBα phosphorylation.