CRAC channels and ca²⁺-dependent gene expression

In order to respond to changes in the environment, cells need to switch genes on and off. One conserved mechanism that links events at the cell surface to gene expression in the nucleus employs intracellular Ca²⁺+. A cytoplasmic Ca²⁺+ rise stimulates Ca²⁺+- dependent transcription factors, which then regulate gene activity. In neurons, Ca²⁺+ entry through voltage-gated Ca²⁺+ channels activates Ca²⁺+-calmodulin-dependent protein kinases, leading to the phosphorylation of the transcription factor CREB (cAMP response-element binding protein) [1,2]. Phosphorylated CREB is thought to be involved in long-term potentiation [3], a form of learning and memory in the nervous system. In immune cells, transcription factors such as c-fos and the nuclear factor of activated T cells (NFAT) are activated by Ca²⁺+ influx through store-operated Ca²⁺+- release-activated Ca²⁺+ (CRAC) channels [4,5]. These transcription factors often work in tandem to control the expression of chemokines and cytokines that are involved in both the innate and adaptive immune responses [6]. NFAT proteins are a family of five cytosolic proteins that migrate into the nucleus upon activation. For four of the members, translocation is triggered by a rise in cytoplasmic Ca²⁺+ concentration [5,7]. NFATs are extensively phosphorylated at rest, resulting in the masking of a nuclear.