Selective recruitment of different Ca²⁺-dependent transcription factors by STIM1-Orai1 channel clusters

Store-operated Ca²⁺ entry, involving endoplasmic reticulum Ca²⁺ sensing STIM proteins and plasma membrane Orai1 channels, is a widespread and evolutionary conserved Ca²⁺ influx pathway. This form of Ca²⁺ influx occurs at discrete loci where peripheral endoplasmic reticulum juxtaposes the plasma membrane. Stimulation evokes numerous STIM1-Orai1 clusters but whether distinct signal transduction pathways require different cluster numbers is unknown. Here, we show that two Ca²⁺-dependent transcription factors, NFAT1 and c-fos, have different requirements for the number of STIM1-Orai1 clusters and on the Ca²⁺ flux through them. NFAT activation requires fewer clusters and is more robustly activated than c-fos by low concentrations of agonist. For similar cluster numbers, transcription factor recruitment occurs sequentially, arising from intrinsic differences in Ca²⁺ sensitivities. Variations in the number of STIM1-Orai1 clusters and Ca²⁺ flux through them regulate the robustness of signalling to the nucleus whilst imparting a mechanism for selective recruitment of different Ca²⁺-dependent transcription factors.