Distinct spatial Ca2+ signatures selectively activate different NFAT transcription factor isoforms

Mol Cell. 2015 Apr 16;58(2):232-43. doi: 10.1016/j.molcel.2015.02.027. Epub 2015 Mar 26.


Protein isoforms are widely expressed in biological systems. How isoforms that co-exist within the same sub-cellular domain are differentially activated remains unclear. Here, we compare the regulatory mechanism of two closely related transcription factor isoforms, NFAT1 and NFAT4, that migrate from the cytoplasm to the nucleus following the increase in intracellular Ca(2+) that accompanies the opening of store-operated Orai1/CRAC channels. We demonstrate that NFAT1 has a private line of communication with Orai1, activating in response to Ca(2+) microdomains near the open channels. By contrast, NFAT4 stimulation requires both local Ca(2+) entry and a nuclear Ca(2+) rise. We mapped differences in nuclear location to amino acids within the SP-3 motif of the NFAT regulatory domain. The different Ca(2+) dependencies enable agonists to recruit different isoform combinations as stimulus strength increases. Our study uncovers a mechanism whereby co-existing cytoplasmic transcription factor isoforms are differentially activated by distinct sub-cellular Ca(2+) signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Calcium / metabolism*
  • Calcium Channels / metabolism*
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • NFATC Transcription Factors / chemistry
  • NFATC Transcription Factors / metabolism*
  • ORAI1 Protein
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism


  • Calcium Channels
  • NFATC Transcription Factors
  • NFATC2 protein, human
  • NFATC3 protein, human
  • ORAI1 Protein
  • ORAI1 protein, human
  • Protein Isoforms
  • Calcium