Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca 2+ Signals

Kar, Pulak; Mirams, Gary R.; Christian, Helen C.; Parekh, Anant B.

Abstract

© 2016 The Author(s) 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.

Citation

Kar, P., Mirams, G. R., Christian, H. C., & Parekh, A. B. (2016). Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca 2+ Signals. Molecular Cell, 64(4), 746-759. https://doi.org/10.1016/j.molcel.2016.11.011

• Journal Article Type: Article
• Acceptance Date: Nov 3, 2016
• Online Publication Date: Nov 17, 2016
• Publication Date: Nov 17, 2016
• Deposit Date: Jan 14, 2020
• Publicly Available Date: Aug 13, 2020
• Journal: Molecular Cell
• Print ISSN: 1097-2765
• Electronic ISSN: 1097-4164
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 64
• Issue: 4
• Pages: 746-759
• DOI: https://doi.org/10.1016/j.molcel.2016.11.011
• Public URL: https://nottingham-repository.worktribe.com/output/3217381
• Publisher URL: https://www.cell.com/molecular-cell/fulltext/S1097-2765(16)30719-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1097276516307195%3Fshowall%3Dtrue
• Additional Information: This article is maintained by: Elsevier; Article Title: Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca2+ Signals; Journal Title: Molecular Cell; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.molcel.2016.11.011; Content Type: article; Copyright: © 2016 The Author(s). Published by Elsevier Inc.