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

Abstract

[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 NFκB transcriptional activity, phosphorylation of IκBα 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 NFκB transcriptional activity through cumulated [Ca2+]i spike-duration-mediated IκBα phosphorylation.