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.

Excitation-transcription coupling, linking stimulation at the cell surface to changes in nuclear gene expression, is conserved throughout eukaryotes. How closely related coexpressed transcription factors are differentially activated remains unclear. Here, we show that two Ca2+-dependent transcription factor isoforms, NFAT1 and NFAT4, require distinct sub-cellular InsP3 and Ca2+ signals for physiologically sustained activation. NFAT1 is stimulated by sub-plasmalemmal Ca2+ microdomains, whereas NFAT4 additionally requires Ca2+ mobilization from the inner nuclear envelope by nuclear InsP3 receptors. NFAT1 is rephosphorylated (deactivated) more slowly than NFAT4 in both cytoplasm and nucleus, enabling a more prolonged activation phase. Oscillations in cytoplasmic Ca2+, long considered the physiological form of Ca2+ signaling, play no role in activating either NFAT protein. Instead, effective sustained physiological activation of NFAT4 is tightly linked to oscillations in nuclear Ca2+. Our results show how gene expression can be controlled by coincident yet geographically distinct Ca2+ signals, generated by a freely diffusible InsP3 message.

Original publication

DOI

10.1016/j.molcel.2016.11.011

Type

Journal article

Journal

Mol Cell

Publication Date

17/11/2016

Volume

64

Pages

746 - 759

Keywords

Animals, Basophils, Bronchi, Calcium, Calcium Signaling, Cell Line, Cell Line, Tumor, Enzyme Inhibitors, Gene Expression Regulation, Green Fluorescent Proteins, HEK293 Cells, Humans, Inositol 1,4,5-Trisphosphate Receptors, Inositol Phosphates, Leukotriene C4, NFATC Transcription Factors, Protein Transport, Rats, Recombinant Fusion Proteins, Thapsigargin, Transcription, Genetic