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

[Ca2+](i) oscillations drive downstream events, like transcription, in a frequency-dependent manner. Why [Ca2+](i) oscillation frequency regulates transcription has not been clearly revealed. A variation in [Ca2+](i) oscillation frequency apparently leads to a variation in the time duration of cumulated [Ca2+](i) elevations or cumulated [Ca2+](i) spike duration. By manipulating [Ca2+](i) spike duration, we generated a series of [Ca2+](i) oscillations with the same frequency but different cumulated [Ca2+](i) spike durations, as well as [Ca2+](i) oscillations with the different frequencies but the same cumulated [Ca2+](i) spike duration. Molecular assays demonstrated that, when generated in 'artificial' models alone, under physiologically simulated conditions or repetitive pulses of agonist exposure, [Ca2+](i) oscillation regulates NF kappa B transcriptional activity, phosphorylation of I kappa B alpha and Ca2+-dependent gene expression all in a way actually dependent on cumulated [Ca2+](i) spike duration whether or not frequency varies. This study underlines that [Ca2+](i) oscillation frequency regulates NF kappa B transcriptional activity through cumulated [Ca2+](i) spike-duration-mediated I kappa B alpha phosphorylation.