Figure 3.

Calcium (Ca²⁺)–calcineurin–nuclear factor of an activated T cell (NFAT) signaling pathway as a novel therapeutic target. Orai1 is a plasma membrane protein with four transmembrane segments. Stromal interaction molecule 1 (STIM1) is a single-pass transmembrane protein located in the endoplasmic reticulum (ER). The increase in intracellular Ca²⁺ concentration by Ca²⁺ entry through Ca²⁺ release-activated Ca²⁺ (CRAC)/Orai1 induces the phosphatase calcineurin. As a result, the activated calcineurin dephosphorylates several serine residues of the NFAT. The NFAT then translocates to the nucleus where it binds to DNA and regulates target gene expression. Some ions or small molecules, including La³⁺, SKF96365, and 2-ABP, are able to inhibit the CRAC channel. Again, already-commercialized cyclosporine A and tacrolimus inhibit calcineurin. Since dysregulated Ca²⁺ signaling is involved in the pathogenesis of autoimmune diseases, intervention of Ca²⁺ signaling in store-operated Ca²⁺ entry (SOCE) through the Orai1–STIM1 pathway may be a promising approach to control autoimmune diseases.