Protein phosphatase 3 catalytic subunit alpha (Calcineurin A) (PPP3CA)

Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase that serves as a critical junction in T-cell activation pathways (UniProt P16298). It consists of a catalytic subunit, Calcineurin A, and a regulatory subunit, Calcineurin B. The enzyme's primary biological role is the dephosphorylation of the Nuclear Factor of Activated T-cells (NFAT), a step required for NFAT's translocation into the nucleus to induce the expression of interleukin-2 (IL-2) and other pro-inflammatory cytokines (StatPearls, Calcineurin Inhibitors). In the context of pharmacology, Calcineurin A is the target of the immunosuppressant Cyclosporine A. Cyclosporine first binds to the intracellular immunophilin Cyclophilin A; this binary complex then binds to Calcineurin A, sterically blocking its active site and inhibiting its phosphatase activity (DrugBank DB00091). This inhibition effectively suppresses the immune response, making it a vital target for preventing organ transplant rejection and managing autoimmune diseases like psoriasis and rheumatoid arthritis (PubMed PMID: 1703530). However, therapeutic use is limited by significant safety concerns, most notably dose-dependent nephrotoxicity and neurotoxicity.

Other names

CalcineurinPPP3CACalcineurin AProtein phosphatase 2B catalytic subunit alphaCALNACNA1CCN1Calcineurin A-Cyclophilin A complex

Inhibition of Calcineurin phosphatase activity through the formation of a drug-immunophilin (Cyclosporine-Cyclophilin A) complex that sterically hinders the enzyme's active site, preventing the dephosphorylation of NFAT.