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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 cells1,2,3,4. 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.

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Figure 1: Generation of synchronized [Ca2+]i oscillations in T cell populations.
Figure 2: [Ca2+]i oscillations enhance the calcium sensitivity of NF-AT-dependent transcription at low levels of stimulation.
Figure 3: Effects of [Ca2+]i and oscillation frequency on NF-AT-, Oct/OAP-, NF-κB-, IL-2- and IL-8-luciferase reporter genes.

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Acknowledgements

We thank J. Goldberg for NF-AT-, Oct/OAP- and NF-κB-luciferase constructs; K.LeClair and G. Crabtree for IL-8 and IL-2 luciferase constructs; C. Fanger for creating the large T antigen and CD8 constructs; G. Crabtree and L. Herzenberg for use of the luminometer and electroporator; S. Finkbeiner, Y. Gotoh and M. Greenberg for comments on the manuscript; and J. Walton for help in preparing constructs. This work was supported by a grant from the NIH (R.S.L.) and by a predoctoral fellowship from the American Heart Association, California Affiliate (R.E.D.).

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Correspondence to Richard S. Lewis.

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Dolmetsch, R., Xu, K. & Lewis, R. Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392, 933–936 (1998). https://doi.org/10.1038/31960

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