TY - JOUR
T1 - CREB decreases astrocytic excitability by modifying subcellular calcium fluxes via the sigma-1 receptor
AU - Eraso-Pichot, Abel
AU - Larramona-Arcas, Raquel
AU - Vicario-Orri, Elena
AU - Villalonga, Rubén
AU - Pardo, Luís
AU - Galea, Elena
AU - Masgrau, R.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - © 2016, Springer International Publishing. 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.
AB - © 2016, Springer International Publishing. 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.
KW - CEPIA indicators
KW - Calcium signalling
KW - Endoplasmic reticulum
KW - MCU
KW - Mitochondria
KW - Mitochondria-associated membranes
KW - VP16-CREB
U2 - 10.1007/s00018-016-2397-5
DO - 10.1007/s00018-016-2397-5
M3 - Article
SN - 1420-682X
VL - 74
SP - 937
EP - 950
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 5
ER -