Kalcineuriin

Kalcineuriin, known in English as calcineurin, is a calcium/calmodulin-dependent serine/threonine protein phosphatase that plays a central role in activating T cells and regulating other calcium-sensitive signaling pathways. It functions as a heterodimer composed of a catalytic A subunit and a regulatory B subunit. In mammals, catalytic subunits include PPP3CA, PPP3CB, and PPP3CC, while regulatory subunits include PPP3R1 and PPP3R2. The enzyme is widely expressed and participates in various cellular processes beyond the immune system.

Activation of kalcineuriin depends on rising intracellular calcium levels. Calcium binds calmodulin, which then activates the enzyme by interacting with the catalytic subunit and relieving an autoinhibitory domain that blocks the active site. Once active, kalcineuriin dephosphorylates a range of substrates, most notably the NFAT family of transcription factors. Dephosphorylated NFAT translocates to the nucleus, where it cooperates with other transcription factors to induce expression of cytokines such as interleukin-2, which are essential for T-cell proliferation and immune responses. The enzyme also participates in other calcium-dependent signaling events in muscle, brain, and other tissues.

Clinical relevance centers on its regulation by immunosuppressants. Cyclosporine A binds to cyclophilin, and tacrolimus (FK506) binds to FKBP12; both drug–immunophilin complexes inhibit kalcineuriin, thereby suppressing NFAT activation and cytokine production. This mechanism underpins the use of these drugs in preventing transplant rejection and treating certain autoimmune conditions. Side effects can include nephrotoxicity, hypertension, and metabolic disturbances. Research on kalcineuriin continues to explore its diverse roles in development, cellular differentiation, and disease.