NFAT activation by membrane potential follows a calcium pathway distinct from other activity-related transcription factors in skeletal muscle cells

Juan Antonio Valdés, Eduardo Gaggero, Jorge Hidalgo, Nancy Leal, Enrique Jaimovich, M. Angélica Carrasco

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29 Citations (Scopus)


Depolarization of skeletal muscle cells triggers intracellular Ca 2+ signals mediated by ryanodine and inositol 1,4,5-trisphosphate (IP3) receptors. Previously, we have reported that K+-induced depolarization activates transcriptional regulators ERK, cAMP response element-binding protein, c-fos, c-jun, and egr-1 through IP3- dependent Ca2+ release, whereas NF-κB activation is elicited by both ryanodine and IP3 receptor-mediated Ca2+ signals. We have further shown that field stimulation with electrical pulses results in an NF-κB activation increase dependent of the amount of pulses and independent of their frequency. In this work, we report the results obtained for nuclear factor of activated T cells (NFAT)-mediated transcription and translocation generated by both K+ and electrical stimulation protocols in primary skeletal muscle cells and C2C12 cells. The Ca2+ source for NFAT activation is through release by ryanodine receptors and extracellular Ca2+ entry. We found this activation to be independent of the number of pulses within a physiological range of stimulus frequency and enhanced by long-lasting low-frequency stimulation. Therefore, activation of the NFAT signaling pathway differs from that of NF-κB and other transcription factors. Calcineurin enzyme activity correlated well with the relative activation of NFAT translocation and transcription using different stimulation protocols. Furthermore, both K+-induced depolarization and electrical stimulation increased mRNA levels of the type 1 IP3 receptor mediated by calcineurin activity, which suggests that depolarization may regulate IP3 receptor transcription. These results confirm the presence of at least two independent pathways for excitation-transcription coupling in skeletal muscle cells, both dependent on Ca2+ release and triggered by the same voltage sensor but activating different intracellular release channels.

Original languageEnglish
Pages (from-to)C715-C725
JournalAmerican Journal of Physiology - Cell Physiology
Issue number3
Publication statusPublished - Mar 2008


  • Calcineurin
  • Inositol 1,4,5-trisphosphate receptor
  • Nuclear factor of activated T cells transcription
  • Nuclear factor of activated T cells translocation
  • Ryanodine receptor

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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