NFAT functions as a working memory of Ca2+ signals in decoding Ca2+ oscillation.

Transcription by the nuclear factor of activated T cells (NFAT) is regulated by the frequency of Ca(2+) oscillation. However, why and how Ca(2+) oscillation regulates NFAT activity remain elusive. NFAT is dephosphorylated by Ca(2+)-dependent phosphatase calcineurin and translocates from the cytoplasm to the nucleus to initiate transcription. We analyzed the kinetics of dephosphorylation and translocation of NFAT. We show that Ca(2+)-dependent dephosphorylation proceeds rapidly, while the rephosphorylation and nuclear transport of NFAT proceed slowly. Therefore, after brief Ca(2+) stimulation, dephosphorylated NFAT has a lifetime of several minutes in the cytoplasm. Thus, Ca(2+) oscillation induces a build-up of dephosphorylated NFAT in the cytoplasm, allowing effective nuclear translocation, provided that the oscillation interval is shorter than the lifetime of dephosphorylated NFAT. We also show that Ca(2+) oscillation is more cost-effective in inducing the translocation of NFAT than continuous Ca(2+) signaling. Thus, the lifetime of dephosphorylated NFAT functions as a working memory of Ca(2+) signals and enables the control of NFAT nuclear translocation by the frequency of Ca(2+) oscillation at a reduced cost of Ca(2+) signaling.