NFAT functions as a working memory of Ca2+ signals in decoding Ca2+ oscillation
NFAT functions as a working memory of Ca2+ signals in decoding Ca2+ oscillation
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DOI：
10.1093/emboj/cdg381
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发表时间：
2003-08-01
期刊：
影响因子：
11.4
通讯作者：
Iino, M
中科院分区：
文献类型：
--
作者：
Tomida, T;Hirose, K;Iino, M
活化T细胞核因子（NFAT）的转录受Ca2+振荡频率的调节。然而，Ca2+振荡为什么以及如何调节NFAT活性仍然难以捉摸。NFAT被Ca2+依赖性磷酸酶钙调磷酸酶去磷酸化，并从细胞质转运到细胞核启动转录。我们分析了NFAT的去磷酸化和易位动力学。我们发现Ca2+依赖性的去磷酸化进行得很快，而NFAT的再磷酸化和核转运进行得很慢。因此，在短暂的Ca2+刺激后，去磷酸化的NFAT在细胞质中的寿命为几分钟。因此，Ca2+振荡诱导细胞质中去磷酸化NFAT的积累，允许有效的核易位，前提是振荡间隔短于去磷酸化NFAT的寿命。我们还表明，Ca2+振荡在诱导NFAT易位方面比连续Ca2+信号传导更具成本效益。因此，去磷酸化NFAT的寿命作为Ca2+信号的工作记忆，并能够通过Ca2+振荡的频率来控制NFAT核易位，同时降低Ca2+信号的成本。
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.