CALCIUM OSCILLATIONS INCREASE THE EFFICIENCY AND SPECIFICITY OF GENE-EXPRESSION

Cytosolic calcium ([Ca2+](i)) oscillations are a nearly universal mode of signalling in excitable and non-excitable cells(1-4). Although Ca2 + is known to mediate a diverse array of cell functions, it is not kno wn whether oscillations contribute to the efficiency or specificity of signalling or are merely an inevitable consequence of the feedback co ntrol of [Ca2+](i). We have developed a Ca2+ clamp technique to invest igate the roles of oscillation amplitude and frequency in regulating g ene expression driven by the proinflammatory transcription factors NF- AT, Oct/GAP and NF-kappa B. Here we report that oscillations reduce th e effective Ca2+ threshold for activating transcription factors, there by increasing signal detection at low levels of stimulation. In additi on, specificity is encoded by the oscillation frequency: rapid oscilla tions stimulate all three transcription factors, whereas infrequent os cillations activate only NF-kappa B. The genes encoding the cytokines interleukin (IL)-2 and IL-8 are also frequency-sensitive in a way that reflects their degree of dependence on NF-AT versus NF-kappa B. Our r esults provide direct evidence that [Ca2+]i oscillations increase both the efficacy and the information content of Ca2+ signals that lead to gene expression and cell differentiation.