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| Subject Categories: Membranes & Transport | Signal Transduction |
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| The EMBO Journal
(2003) 22, 3825–3832, doi:10.1093/emboj/cdg381 |
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| NFAT functions as a working memory of Ca2+ signals in decoding Ca2+ oscillation |
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| Taichiro Tomida1, Kenzo Hirose1, Azusa Takizawa1, Futoshi Shibasaki2 and Masamitsu Iino1 |
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1 Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan 2 Department of Molecular Cell Physiology, The Tokyo Metropolitan Institute of Medical Science, Bunkyo-kuv, Tokyo 113-8613, Japan To whom correspondence should be addressed Masamitsu Iino, iino@m.u-tokyo.ac.jp Received 12 March 2003; Revised 2 June 2003; Accepted 11 June 2003. |
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| Abstract |
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| 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. |
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| Keywords: calcineurin, Ca2+ oscillation, frequency dependence, NFAT, nuclear translocation |
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