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

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 dephosphorylation proceeds rapidly, while the rephosphorylation and nuclear transport of NFAT proceed slowly. Therefore, after brief Ca2+ stimulation, dephosphorylated 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 dephosphorylated 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.