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.