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

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Abstract
Transcription by the nuclear factor of activated T cells (NFAT) is regulated by the frequency of Ca2+ oscillation. However, why and how Ca2+ oscillation regulates NFAT activity remain elusive. NFAT is dephosphorylated by Ca2+‐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 Ca2+‐dependent dephosphoryl ation proceeds rapidly, while the rephosphorylation and nuclear transport of NFAT proceed slowly. Therefore, after brief Ca2+ stimulation, dephosphoryl ated NFAT has a lifetime of several minutes in the cytoplasm. Thus, Ca2+ 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 dephos phorylated NFAT. We also show that Ca2+ oscillation is more cost‐effective in inducing the translocation of NFAT than continuous Ca2+ signaling. Thus, the lifetime of dephosphorylated NFAT functions as a working memory of Ca2+ signals and enables the control of NFAT nuclear translocation by the frequency of Ca2+ oscillation at a reduced cost of Ca2+ signaling.