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 Ca(2+)-dependent transcription factor isoforms, NFAT1 and NFAT4, require distinct sub-cellular InsP3 and Ca(2+) signals for physiologically sustained activation. NFAT1 is stimulated by sub-plasmalemmal Ca(2+) microdomains, whereas NFAT4 additionally requires Ca(2+) 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 Ca(2+), long considered the physiological form of Ca(2+) signaling, play no role in activating either NFAT protein. Instead, effective sustained physiological activation of NFAT4 is tightly linked to oscillations in nuclear Ca(2+). Our results show how gene expression can be controlled by coincident yet geographically distinct Ca(2+) signals, generated by a freely diffusible InsP3 message.

Original publication

DOI

10.1016/j.molcel.2016.11.011

Type

Journal article

Journal

Molecular Cell

Publisher

Elsevier (Cell Press)

Publication Date

17/11/2016

Volume

64

Pages

746 - 759