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Cell Mol Life Sci. 2017 Mar;74(5):937-950. doi: 10.1007/s00018-016-2397-5. Epub 2016 Oct 19.

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

Author information

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.
2
Department of Neurosciences, School of Medicine, University of California, 9500 Gilman Dr, La Jolla, CA, 92093, USA.
3
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. galea.inc@gmail.com.
4
Institució Catalana De Recerca I Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010, Barcelona, Catalonia, Spain. galea.inc@gmail.com.
5
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. roser.masgrau@uab.cat.

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.

KEYWORDS:

CEPIA indicators; Calcium signalling; Endoplasmic reticulum; MCU; Mitochondria; Mitochondria-associated membranes; VP16-CREB

PMID:
27761593
DOI:
10.1007/s00018-016-2397-5
[Indexed for MEDLINE]

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