CRAC Channels and Ca2+-Dependent Gene Expression

Excerpt

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 localization sequence. A rise in Ca²⁺ activates the enzyme calcineurin, the target of immunosuppressants cyclosporine A and tacrolimus. Dephosphorylation exposes nuclear localization sequences, enabling NFAT to migrate into the nucleus in a complex with tubulin alpha [8]. Activator protein-1 (AP-1) is a transcription complex composed of members of the fos and jun families that can associate to form a range of homo- and heterodimers [9]. AP-1 activity can be increased by the stimulation of preexisting protein or following enhanced expression and many extracellular signals including G-protein-coupled receptor agonists, cytokines, and growth factors target AP-1 activity. Here, the involvement of cytoplasmic Ca²⁺, particularly localized Ca²⁺ signals or Ca²⁺ microdomains, in activating NFAT and c-fos will be described. The focus is on immune cells, where these processes have been studied in considerable detail.