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

T Tomida, K Hirose, A Takizawa, F Shibasaki… - The EMBO …, 2003 - embopress.org
T Tomida, K Hirose, A Takizawa, F Shibasaki, M Iino
The EMBO journal, 2003embopress.org
Transcription by the nuclear factor of activated T cells (NFAT) is regulated by the frequency
of Ca 2+ oscillation. However, why and how Ca 2+ oscillation regulates NFAT activity remain
elusive. NFAT is dephosphorylated by Ca 2+‐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 Ca 2+‐dependent
dephosphoryl ation proceeds rapidly, while the rephosphorylation and nuclear transport of …
Abstract
Transcription by the nuclear factor of activated T cells (NFAT) is regulated by the frequency of Ca 2+ oscillation. However, why and how Ca 2+ oscillation regulates NFAT activity remain elusive. NFAT is dephosphorylated by Ca 2+‐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 Ca 2+‐dependent dephosphoryl ation proceeds rapidly, while the rephosphorylation and nuclear transport of NFAT proceed slowly. Therefore, after brief Ca 2+ stimulation, dephosphoryl ated NFAT has a lifetime of several minutes in the cytoplasm. Thus, Ca 2+ 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 Ca 2+ oscillation is more cost‐effective in inducing the translocation of NFAT than continuous Ca 2+ signaling. Thus, the lifetime of dephosphorylated NFAT functions as a working memory of Ca 2+ signals and enables the control of NFAT nuclear translocation by the frequency of Ca 2+ oscillation at a reduced cost of Ca 2+ signaling.
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