Calcineurin (Protein phosphatase 2B) (CaN)

Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase that serves as a critical link between intracellular calcium signaling and the adaptive immune response (UniProt: P16298). It is a heterodimer composed of a catalytic subunit (Calcineurin A) and a regulatory calcium-binding subunit (Calcineurin B). In T cells, activation of the T cell receptor leads to an influx of calcium, which activates calcineurin to dephosphorylate the Nuclear Factor of Activated T-cells (NFAT). Once dephosphorylated, NFAT translocates from the cytoplasm to the nucleus, where it promotes the expression of interleukin-2 (IL-2) and other cytokines essential for T cell proliferation and differentiation (PubMed: 15240697). Due to its central role in immune activation, calcineurin is the primary target for major immunosuppressive drugs such as cyclosporine and tacrolimus, which are used to prevent rejection in solid organ transplantation and to treat various autoimmune conditions (StatPearls: NBK553062). However, the clinical use of calcineurin inhibitors is frequently complicated by significant side effects, including dose-dependent nephrotoxicity and hypertension, which require careful monitoring of drug levels in patients.

Other names

Protein phosphatase 2BPPP3CAPPP3CBPPP3CCCalcium-dependent serine-threonine phosphataseCalmodulin-dependent protein phosphatase

Calcineurin inhibitors bind to intracellular immunophilins (cyclophilin for cyclosporine or FKBP12 for tacrolimus) to form a complex that sterically inhibits the phosphatase activity of calcineurin, thereby preventing the dephosphorylation of Nuclear Factor of Activated T-cells (NFAT) and its subsequent translocation to the nucleus to initiate cytokine transcription.