Mg2+ deprivation elicits rapid Ca2+ uptake and activates Ca2+/calcineurin signaling in Saccharomyces cerevisiae

To learn about the cellular processes involved in Mg2+ homeostasis and the mechanisms allowing cells to cope with low Mg2+ availability, we performed RNA expression-profiling experiments and followed changes in gene activity upon Mg2+ depletion on a genome-wide scale. A striking portion of genes up-regulated under Mg2+ depletion are also induced by high Ca2+ and/or alkalinization. Among the genes significantly upregulated by Mg2+ starvation, Ca2+ stress, and alkalinization are ENA1 (encoding a P-type ATPase sodium pump) and PH089 (encoding a sodium/phosphate cotransporter). We show that up-regulation of these genes is dependent on the calcineurin/Crz1p (calcineurin-responsive zinc finger protein) signaling pathway. Similarly to Ca2+ stress, Mg2+ starvation induces translocation of the transcription factor Crz1p from the cytoplasm into the nucleus. The up-regulation of ENA1 and PH089 upon Mg2+ starvation depends on extracellular Ca. Using fluorescence resonance energy transfer microscopy, we demonstrate that removal of Mg2+ results in an immediate increase in free cytoplasmic Ca2+. This effect is dependent on external Ca2+. The results presented indicate that Mg2+ depletion in yeast cells leads to enhanced cellular Ca2+ concentrations, which activate the Crz1p/calcineurin pathway. We provide evidence that calcineurin/Crz1p signaling is crucial for yeast cells to cope with Mg2+ depletion stress.