Calcineurin–NFAT signaling pathway (CN-NFAT pathway)

The Calcineurin–NFAT signaling pathway is a central intracellular cascade that integrates calcium signals to regulate gene expression, primarily in T lymphocytes [1, 18]. Upon T-cell receptor (TCR) stimulation, an increase in intracellular calcium activates calcineurin, a calcium/calmodulin-dependent serine/threonine phosphatase [2, 20]. Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT) family, triggering their translocation from the cytoplasm to the nucleus [8, 11]. Once in the nucleus, NFAT proteins cooperate with other transcription factors to induce the expression of key cytokines, such as interleukin-2 (IL-2), which are essential for T-cell activation, proliferation, and the adaptive immune response [9, 11]. This pathway is the primary target of immunosuppressive drugs like cyclosporine and tacrolimus, which inhibit calcineurin to prevent organ transplant rejection and treat autoimmune disorders [4, 5, 10]. However, systemic inhibition of this pathway is associated with significant safety concerns, including nephrotoxicity, neurotoxicity, and hypertension [19, 22]. Beyond its role in immunity, the calcineurin–NFAT axis is involved in diverse biological processes such as cardiac development, bone remodeling, and the progression of certain malignancies [18, 24, 26].

Other names

Calcineurin/NFAT axisCa2+/calcineurin/NFAT pathwayProtein phosphatase 3 signalingNuclear factor of activated T-cells signaling

Calcineurin inhibitors (CNIs) bind to intracellular immunophilins (cyclophilin or FKBP12) to form a complex that inhibits the phosphatase activity of calcineurin [4, 8]. This prevents the dephosphorylation of NFAT transcription factors, blocking their nuclear translocation and the subsequent transcription of pro-inflammatory cytokines like interleukin-2 (IL-2) [5, 11].