Category: signaling
Calcineurin (PP2B) is a Ca²⁺/calmodulin-dependent serine/threonine phosphatase — the canonical T-cell activation switch and the molecular target of cyclosporine A + tacrolimus. T-cell activation flow: TCR engagement → LCK / ZAP70 / LAT → PLCγ1 → IP3 → ER Ca²⁺ release → STIM1 / STIM2 oligomerization → ORAI1 channel activation at plasma membrane → sustained Ca²⁺ influx (CRAC current, store-operated). Sustained cytoplasmic Ca²⁺ → calmodulin binds + activates calcineurin. Active calcineurin dephosphorylates the regulatory domain of NFAT (NFATc1-c4 isoforms) at multiple Ser sites → unmasks nuclear-localization signal → NFAT nuclear translocation → cooperates with AP-1 (Fos-Jun, PMA-inducible) at composite NFAT-AP-1 sites → drives IL-2, IL-4, IFN-γ, CD40L, FasL, GM-CSF transcription → T-cell proliferation + effector differentiation. Immunosuppressants — direct calcineurin inhibitors (CNIs): cyclosporine binds cyclophilin A → cyclo-CypA complex inhibits calcineurin; tacrolimus binds FKBP12 → tacro-FKBP12 complex inhibits calcineurin (same active site, different immunophilin). Side-effect profile (similar across CNIs): nephrotoxicity (vasoconstriction + tubular toxicity), neurotoxicity, HTN, hyperglycemia (post-transplant diabetes), hyperlipidemia, gingival hyperplasia (cyclosporine > tacrolimus), hirsutism (cyclosporine), alopecia + tremor (tacrolimus). Pimecrolimus is the topical FKBP-calcineurin inhibitor for atopic dermatitis. mTOR inhibitors (rapamycin, everolimus) act downstream of FKBP12 but inhibit mTORC1, NOT calcineurin — different mechanism. JAK inhibitors block downstream cytokine signaling (parallel target). Cross-links: [[cyp_phase1_overview]] (CYP3A4 metabolism — many DDIs), [[transporter_phase3_overview]] (P-gp substrates), [[mtor_signaling]] (parallel arm), [[insulin_glucose_homeostasis]] (post-transplant DM).