Differential activation of transcription factors induced by Ca2+ response amplitude and duration

An increase in the intracellular calcium ion concentration ([Ca 2+ ] i ) controls a diverse range of cell functions, including adhesion, motility, gene expression and proliferation 1,2 . Calcium signalling patterns can occur as single transients, repetitive oscillations or sustained plateaux 2,3 , but it is not known whether these patterns are responsible for encoding the specificity of cellular responses. We report here that the amplitude and duration of calcium signals in B lymphocytes controls differential activation of the pro–inflammatory transcriptional regulators NF-κB, c-Jun N-terminal kinase (JNK) and NFAT. NF-κB and JNK are selectively activated by a large transient [Ca 2+ ] i rise, whereas NFAT is activated by a low, sustained Ca 2+ plateau. Differential activation results from differences in the Ca 2+ sensitivities and kinetic behaviour of the three pathways. Our results show how downstream effectors can decode information contained in the amplitude and duration of Ca 2+ signals, revealing a mechanism by which a multifunctional second messenger such as Ca 2+ can achieve specificity in signalling to the nucleus.