Protein phosphatase 3 (Calcineurin) (PPP3)

Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a central role in the activation of T-lymphocytes and the overall immune response (UniProt, 2023). It exists as a heterodimer consisting of a catalytic subunit, Calcineurin A (PPP3CA, PPP3CB, or PPP3CC), and a regulatory calcium-binding subunit, Calcineurin B (PPP3R1 or PPP3R2). Upon stimulation of the T-cell receptor, intracellular calcium levels rise, activating calcineurin to dephosphorylate the Nuclear Factor of Activated T-cells (NFAT). Dephosphorylated NFAT then translocates to the nucleus, where it promotes the expression of interleukin-2 (IL-2) and other cytokines essential for T-cell proliferation (PMID: 17408404). Due to this critical function, calcineurin is the primary target for immunosuppressive drugs like cyclosporine and tacrolimus, which are used to prevent organ transplant rejection and treat autoimmune diseases. However, the ubiquitous expression of calcineurin in other tissues leads to significant therapeutic challenges, most notably dose-limiting nephrotoxicity and neurotoxicity (StatPearls, 2023).

Other names

CalcineurinProtein phosphatase 2BPP2BCalcium/calmodulin-dependent serine/threonine protein phosphatase

Cyclosporine and other calcineurin inhibitors bind to intracellular immunophilins (e.g., cyclophilin for cyclosporine) to form a complex that specifically inhibits the phosphatase activity of calcineurin. This inhibition prevents the dephosphorylation of the transcription factor NFAT (Nuclear Factor of Activated T-cells), thereby blocking its translocation into the nucleus and the subsequent transcription of interleukin-2 (IL-2) and other cytokines required for T-cell activation and proliferation (StatPearls, 2023; PMID: 23539241).