PP2Bcalcineurin

Calcineurin, also known as protein phosphatase 2B (PP2B), is a highly conserved calcium/calmodulin-dependent serine/threonine phosphatase found in most eukaryotic cells. The enzyme functions as a heterodimer composed of a catalytic A subunit (CnA) and a regulatory B subunit (CnB). There are multiple catalytic and regulatory isoforms (e.g., PPP3CA and PPP3CB for the A subunits; PPP3R1 and PPP3R2 for the B subunits) that combine to form holoenzymes with differing tissue distribution and calcium sensitivity.

Activation requires a rise in intracellular calcium that binds to calmodulin, which then binds to the catalytic subunit and relieves its autoinhibitory domain, enabling phosphate release from substrate proteins. The B subunit contributes to calcium sensing and substrate selection.

Calcineurin dephosphorylates a variety of substrates, but is best known for activating the NFAT family of transcription factors in T cells. Dephosphorylated NFAT translocates to the nucleus and promotes transcription of cytokine genes such as IL-2, supporting T-cell activation. In neurons and other tissues, calcineurin regulates synaptic plasticity, gene expression, and membrane receptor trafficking, notably affecting LTD and AMPA receptor function.

Regulation is governed by calcium signaling and calmodulin binding; pharmacological inhibitors such as cyclosporin A (in complex with cyclophilin) and tacrolimus (FKBP12) bind to the enzyme and block its activity, producing immunosuppression. Dysregulation of calcineurin has been linked to immune disorders, developmental defects, and cardiac hypertrophy, among others.

Calcineurin remains a central node in calcium-dependent signaling, bridging intracellular calcium fluctuations to transcriptional and physiological responses.