Different agonists recruit different stromal interaction molecule proteins to support cytoplasmic Ca2+ oscillations and gene expression.

Stimulation of cells with physiological concentrations of calcium-mobilizing agonists often results in the generation of repetitive cytoplasmic Ca2+ oscillations. Although oscillations arise from regenerative Ca2+ release, they are sustained by store-operated Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels. Here, we show that following stimulation of cysteinyl leukotriene type I receptors in rat basophilic leukemia (RBL)-1 cells, large amplitude Ca2+ oscillations, CRAC channel activity, and downstream Ca2+-dependent nuclear factor of activated T cells (NFAT)-driven gene expression are all exclusively maintained by the endoplasmic reticulum Ca2+ sensor stromal interaction molecule (STIM) 1. However, stimulation of tyrosine kinase-coupled FCeRI receptors evoked Ca2+ oscillations and NFAT-dependent gene expression through recruitment of both STIM2 and STIM1. We conclude that different agonists activate different STIM proteins to sustain Ca2+ signals and downstream responses.