The Ca2+–calcineurin–NFAT signalling pathway

Abstract

Abstract Most if not all eukaryotic cells utilize Ca2+ as a second messenger but the mechanisms employed to control Ca2+ levels and the downstream molecules used to transmit the Ca2+ signal vary between different cell types and tissues. A major pathway for Ca2+ entry in non-excitable cells is store-operated Ca2+ entry (SOCE) via the opening of Ca2+ release activated Ca2+ (CRAC) channels. Subsequent elevation of intracellular Ca2+ levels results in the activation of a large number of calmodulin (CaM)-dependent enzymes including the serine-threonine phosphatase calcineurin. The transcription factor NFAT (nuclear factor of activated T cells) is dephosphorylated and activated by calcineurin and in turn controls expression of numerous genes. Sustained Ca2+ influx and NFAT activation are crucial for lymphocyte activation and many other cellular processes including protein secretion, cell metabolism, cell differentiation as well as opposite processes like activation induced cell death or T cell unresponsiveness. In this chapter we will describe the Ca2+-calcineurin-NFAT pathway using the immune system, where it was first described and is best characterized, as a model.