Activation of nuclear Ca²⁺-dependent gene expression by CRAC channel Ca²⁺ nanodomains

Oscillations in the levels of second messengers are observed throughout the phylogenetic tree, with signaling information encoded in the frequency of the spikes. Different biological targets respond to different frequencies of oscillation, leading to the concept of frequency counting. The most widely observed and best understood oscillatory second messenger is cytosolic Ca²⁺. Ca²⁺ oscillations are generated in all cell types, are seen throughout the life of a cell, and are indispensable for diverse biological processes ranging from fertilization to cell death and myriad responses in between including excitation-transcription coupling through Ca²⁺-dependent gene expression. The widely expressed Ca²⁺-dependent transcription factors nuclear factor (NF) of activated T cells (NFAT) and NF-κB are recruited by different Ca²⁺ oscillation frequencies, increasing the signaling bandwidth through the universal Ca²⁺ messenger. Here, we show that Ca²⁺ nanodomains near Ca²⁺ channels at the cell surface are central to gene expression. Cytosolic Ca²⁺ oscillations are not necessary for Ca²⁺-dependent gene expression, provided Ca²⁺ nanodomains near Ca²⁺ release-activated Ca²⁺ (CRAC) channels are formed. Our results establish that a fundamental unit of excitation-transcription coupling is the Ca²⁺ channel nanodomain at the cell surface.