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

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.

Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function

“…The Sigmar1 gene has a CREBbinding site in its promoter region; METH-mediated activation of astrocytes involved CREB translocated into the nucleus and interaction with the promoter of Sigmar1, resulting in increased expression of Sigmar1 66 . Similarly, Sigmar1 upregulation was observed in cultured astrocytes from adult rats after infection with the VP16-CREB viral vector, and in transgenic mice with targeted activation of CREB in astrocytes 67 . All of these studies suggest a CREB-Sigmar1 feedback loop regulating their own expression modulated by METH exposure.…”

GSEA of mouse and human mitochondriomes reveals fatty acid oxidation in astrocytes

“…Moreover, a recent study in isolated mitochondria has revealed comparable oxidative phosphorylation in astrocytes and neurons, despite molecular differences in ETC complexes (Lopez-Fabuel et al, 2016). And, finally, astrocyte mitochondria have an active role in calcium signaling (Agarwal et al, 2017;Eraso-Pichot et al, 2017). This is a key element of astrocyte excitability, mediating astrocyte actions in the so-called cerebrovascular unit that controls the coupling of brain metabolism with blood flow (Belanger et al, 2011).…”

Glutamate Carrier Involvement in Mitochondrial Dysfunctioning in the Brain White Matter

“…The AGC1 promotor regions contain a CRE site, which in neurons leads to increased AGC1 expression after binding of CREB upon its calcium-induced phosphorylation (Menga et al, 2015). CREB-dependent transcription additionally upregulates Sigma-1 receptor expression, and leads to lowered astrocytic excitability by decreasing ATP-dependent subcellular calcium waves (Eraso-Pichot et al, 2017). ATF4 is another CREB protein.…”