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Calcineurin controls gene transcription following stimulation of a Gαq-coupled designer receptor

Langfermann, Daniel S., Schmidt, Tobias, Rössler, Oliver G., Thiel, Gerald·2019·Experimental Cell Research
DOI 10.1016/j.yexcr.2019.111553
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Abstract

Stimulation of Gaq-coupled receptors triggers the activation of gene transcription via a rise of intracellular Ca 2+ . To investigate the role of the Ca 2+ /calmodulin-dependent phosphatase calcineurin in regulating transcription following Gαq-coupled receptor stimulation, we used a gain-of-function approach and expressed ΔCnA, a constitutively active mutant of calcineurin A. Furthermore, we expressed hM3Dq, a designer receptor that is specifically coupled to Gαq and can be activated by the pharmacological compound clozapine-N-oxide. Stimulation of hM3Dq or expression of ΔCnA induced transcription of a reporter gene controlled by the calcineurin substrate nuclear factor of activated T cells (NFAT), suggesting that calcineurin increased NFAT-regulated gene transcription. In contrast, expression of ΔCnA attenuated hM3Dq-induced biosynthesis of the transcription factors c-Fos and Egr-1 and reduced both c-Fos and Egr-1 promoter activities. A dissection of the c-Fos and Egr-1 promoters revealed that calcineurin inhibited serum response element-mediated transcription. In particular, the expression of ΔCnA reduced the transcriptional activity of the ternary complex factor Elk-1 following stimulation of hM3Dq receptors. Furthermore, ΔCnA reduced the transcriptional activity of the transcription factor CREB and thus attenuated transcription mediated by the cAMP response element. In summary, we show that calcineurin functions as a positive and negative modulator of gene transcription.

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Cited by

Metadata

Authors
Langfermann, D. S., Schmidt, T., Rössler, O. G., & Thiel, G.
Venue
Experimental Cell Research
Publisher
Elsevier BV
Published
2019-10
Volume
383
Issue
2
Pages
111553
ISSN
0014-4827
DOI
10.1016/j.yexcr.2019.111553
Cited by
11
References
0
Language
en
Licence
Funders
Universität des Saarlandes

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