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CREB decreases astrocytic excitability by modifying subcellular calcium fluxes via the sigma-1 receptor

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Abstract

Astrocytic excitability relies on cytosolic calcium increases as a key mechanism, whereby astrocytes contribute to synaptic transmission and hence learning and memory. While it is a cornerstone of neurosciences that experiences are remembered, because transmitters activate gene expression in neurons, long-term adaptive astrocyte plasticity has not been described. Here, we investigated whether the transcription factor CREB mediates adaptive plasticity-like phenomena in astrocytes. We found that activation of CREB-dependent transcription reduced the calcium responses induced by ATP, noradrenaline, or endothelin-1. As to the mechanism, expression of VP16-CREB, a constitutively active CREB mutant, had no effect on basal cytosolic calcium levels, extracellular calcium entry, or calcium mobilization from lysosomal-related acidic stores. Rather, VP16-CREB upregulated sigma-1 receptor expression thereby increasing the release of calcium from the endoplasmic reticulum and its uptake by mitochondria. Sigma-1 receptor was also upregulated in vivo upon VP16-CREB expression in astrocytes. We conclude that CREB decreases astrocyte responsiveness by increasing calcium signalling at the endoplasmic reticulum–mitochondria interface, which might be an astrocyte-based form of long-term depression.

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Abbreviations

ER:

Endoplasmic reticulum

IP3 :

Inositol 1,4,5-trisphosphate

CRE:

cAMP regulatory element

CREB:

cAMP regulatory element-binding protein

LTD:

Long-term depression

NA:

Noradrenaline

PKA:

Protein-kinase A

PKC:

Protein-kinase C

MSK1:

Mitogen- and stress-activated protein kinase

RSK2:

Ribosomal protein S6 kinase

FBS:

Fetal bovine serum

ET-1:

Endothelin-1

Glu:

Glutamate

FCCP:

Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone

GPN:

Gly-phe-β-naphthylamide

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

CEPIA:

Calcium-measuring organelle-entrapped protein indicators

PBS:

Phosphate-buffered saline

NGS:

Normal goat serum

GPCR:

Gq protein-coupled receptors

MCU:

Mitochondrial calcium uniporter

NAADP:

Nicotinic acid adenine dinucleotide phosphate

MAM:

Mitochondria-associated ER membranes

WT:

Wild-type

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Acknowledgments

This research was funded by Grants BFU2010-21921 and BFU2012-38844 from the Ministerio de Economía y Competitividad, Gobierno de España (Co-funded with European Regional Development’s Fund, FEDER), and Grants 2005SGR-00719 and 2014SGR-00984 from the Generalitat de Catalunya AGAUR. Abel Eraso is a recipient of the fellowship FPU13/05377 from the Ministerio de Educación, Cultura y Deporte, Gobierno de España and Raquel Larramona recipient of a fellowship from La Marató de TV3 (TV3-20141430). We thank Dr. Grant Churchill for providing us with Ned-19 and for critical reading of the manuscript and Cristina Gutiérrez for assistance in tissue culture.

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Author notes

  1. E. Vicario-Orri

    Present address: Department of Neurosciences, School of Medicine, University of California, 9500 Gilman Dr, La Jolla, CA, 92093, USA

Authors and Affiliations

  1. Unitat de Bioquímica de Medicina, Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Edifici M, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Catalonia, Spain

    A. Eraso-Pichot, R. Larramona-Arcas, E. Vicario-Orri, R. Villalonga, L. Pardo, E. Galea & R. Masgrau

  2. Institució Catalana De Recerca I Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010, Barcelona, Catalonia, Spain

    E. Galea

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  1. A. Eraso-Pichot
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Eraso-Pichot, A., Larramona-Arcas, R., Vicario-Orri, E. et al. CREB decreases astrocytic excitability by modifying subcellular calcium fluxes via the sigma-1 receptor. Cell. Mol. Life Sci. 74, 937–950 (2017). https://doi.org/10.1007/s00018-016-2397-5

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