Decoding of Cytoplasmic Ca2+ Oscillations through the Spatial Signature Drives Gene Expression

SummaryCytoplasmic Ca2+ oscillations are a universal signaling mode that activates numerous cellular responses 1 and 2. Oscillations are considered the physiological mechanism of Ca2+ signaling because they occur at low levels of stimulus intensity [3]. Ca2+ oscillations are proposed to convey information in their amplitude and frequency, leading to activation of specific downstream targets 4, 5 and 6. Here, we report that the spatial Ca2+ gradient within the oscillation is key. Ca2+ oscillations in mast cells evoked over a range of agonist concentrations in the presence of external Ca2+ were indistinguishable from those in the absence of Ca2+ when plasmalemmal Ca2+ extrusion was suppressed. Nevertheless, only oscillations with accompanying Ca2+ entry through store-operated CRAC channels triggered gene expression. Increased cytoplasmic Ca2+ buffering prevented oscillations but not gene activation. Local Ca2+ influx and not global Ca2+ oscillations therefore drives gene expression at physiological levels of stimulation. Rather than serving to maintain Ca2+ oscillations by replenishing stores, we suggest that the role of oscillations might be to activate CRAC channels, thereby ensuring the generation of spatially restricted physiological Ca2+ signals driving gene activation. Furthermore, we show that the spatial profile of a Ca2+ oscillation provides a novel mechanism whereby a pleiotropic messenger specifically activates gene expression.