Abstract
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.
Highlights
Store-operated Ca2+ entry, involving endoplasmic reticulum Ca2+ sensing STIM proteins and plasma membrane Orai[1] channels, is a widespread and evolutionary conserved Ca2+ influx pathway
We reasoned that modest store depletion under hyperpolarised conditions in RBL cells should produce an equivalent rise in bulk cytosolic Ca2+ as strong store depletion under depolarised conditions, because large Ca2+ flux through few channels should raise bulk Ca2+ to a similar extent as reduced flux through many channels
Transcription of some genes is regulated by nuclear factor of activated T cells (NFAT) and c-fos acting in combination, others are activated only by NFAT32
Summary
Store-operated Ca2+ entry, involving endoplasmic reticulum Ca2+ sensing STIM proteins and plasma membrane Orai[1] channels, is a widespread and evolutionary conserved Ca2+ influx pathway. We show that two Ca2+-dependent transcription factors, NFAT1 and c-fos, have different requirements for the number of STIM1-Orai[1] clusters and on the Ca2+ flux through them. Variations in the number of STIM1-Orai[1] 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. Ca2+ microdomains near open CRAC channels activate downstream signalling pathways, including certain isoforms of adenylyl cyclase[11], plasma membrane Ca2+ ATPase pumps[12], Ca2+-dependent phospholipase A213 and endothelial NO synthase[14]. AKAP-79 interacts with Orai[1], resulting in activation of calcineurin by Ca2+ microdomains near the open channels
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