Calcium oscillations increase the efficiency and specificity of gene expression

Abstract

Cytosolic calcium ([Ca²⁺]_i) oscillations are a nearly universal mode of signalling in excitable and non-excitable cells^1,2,3,4. Although Ca²⁺ is known to mediate a diverse array of cell functions, it is not known whether oscillations contribute to the efficiency or specificity of signalling or are merely an inevitable consequence of the feedback control of [Ca²⁺]_i. We have developed a Ca²⁺ clamp technique to investigate the roles of oscillation amplitude and frequency in regulating gene expression driven by the proinflammatory transcription factors NF-AT, Oct/OAP and NF-κB. Here we report that oscillations reduce the effective Ca²⁺ threshold for activating transcription factors, thereby increasing signal detection at low levels of stimulation. In addition, specificity is encoded by the oscillation frequency: rapid oscillations stimulate all three transcription factors, whereas infrequent oscillations activate only NF-κB. 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-κB. Our results 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.