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

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