Inhibition of the calcineurin-NFATc pathway at multiple levels. Upon receptor induced Ca2+ entry into the cell, calmodulin (CaM) and calcineurin B (CaNB) bind Ca2+ ions and activate calcineurin by inducing a conformational switch of the subunit A (CaNA). Activated calcineurin binds NFATc via the PxIxIT and the LxVP motifs of NFATc and subsequently dephosphorylates the transcription factor. Dephosphorylated NFATc exposes its nuclear localization sequence (NLS) and is therefore shuttled into the nucleus, where it binds to the appropriate DNA sequences. NFATc exerts its transactivation effects often in combination with another transcription factor (TF). NFATc is deactivated by rephosphorylation and subsequent translocation into the cytosol. Different steps in this pathway are targeted by certain compounds to finally suppress NFATc-dependent gene expression. A selection of the most important and best characterized inhibitors of calcineurin-NFATc signalling is shown (in red) at their point of interference. AID: autoinhibitory domain of calcineurin A; TCR: T cell receptor.