calcineuriin

Calcineurin, occasionally spelled calcineuriin in older sources, is a calcium/calmodulin-dependent serine/threonine protein phosphatase that mediates calcium signaling in many cells. It is a heterodimer composed of a catalytic A subunit (CnA) and a regulatory B subunit (CnB). The enzyme requires divalent metal ions, typically Mg2+, for catalysis. Activation begins when intracellular Ca2+ rises and Ca2+/calmodulin binds to the catalytic subunit, relieving autoinhibition and triggering phosphatase activity.

Calcineurin dephosphorylates members of the NFAT family, enabling their translocation to the nucleus where they promote transcription of cytokine genes such as IL-2, a central step in T cell activation. The pathway also participates in gene regulation in neurons and other tissues.

Regulation occurs via endogenous inhibitors and scaffolding proteins; RCAN (DSCR1) proteins can inhibit calcineurin, and subcellular localization is organized by AKAP scaffolds. Pharmacological inhibitors—cyclosporine A bound to cyclophilin, and tacrolimus bound to FKBP12—form complexes that bind and inhibit calcineurin, producing immunosuppression. These drugs are used to prevent transplant rejection and to treat certain autoimmune disorders.

Clinical relevance: Calcineurin signaling is essential for adaptive immune responses; loss of function impairs T cell activation, while dysregulated activity is implicated in cardiac hypertrophy and CNS development. Ongoing research seeks more selective modulators to reduce side effects of current inhibitors.