Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication




Journal article


Mol Cell

Publication Date





232 - 243


Amino Acid Motifs, Calcium, Calcium Channels, Cell Nucleus, Cytoplasm, Gene Expression Regulation, HEK293 Cells, Humans, NFATC Transcription Factors, ORAI1 Protein, Protein Isoforms