ATP and noradrenaline activate CREB in astrocytes via noncanonical Ca²⁺ and cyclic AMP independent pathways

Abstract

In neurons, it is well established that CREB contributes to learning and memory by orchestrating the translation of experience into the activity-dependent (i.e., driven by neurotransmitters) transcription of plasticity-related genes. The activity-dependent CREB-triggered transcription requires the concerted action of cyclic AMP/protein kinase A and Ca(2+) /calcineurin via the CREB-regulated transcription co-activator (CRTC). It is not known, however, whether a comparable molecular sequence occurs in astrocytes, despite the unquestionable contribution of these cells to brain plasticity. Here we sought to determine whether and how ATP and noradrenaline cause CREB-dependent transcription in rat cortical astrocyte cultures. Both transmitters induced CREB phosphorylation (Western Blots), CREB-dependent transcription (CRE-luciferase reporter assays), and the transcription of Bdnf, a canonical regulator of synaptic plasticity (quantitative RT-PCR). We indentified a Ca(2+) and diacylglycerol-independent protein kinase C at the uppermost position of the cascade leading to CREB-dependent transcription. Notably, CREB-dependent transcription was partially dependent on ERK1/2 and CRTC, but independent of cyclic AMP/protein kinase A or Ca(2+) /calcineurin. We conclude that ATP and noradrenaline activate CREB-dependent transcription in cortical astrocytes via an atypical protein kinase C. It is of relevance that the signaling involved be starkly different to the one described in neurons since there is no convergence of Ca(2+) and cyclic AMP-dependent pathways on CRTC, which, moreover, exerts a modulatory rather than a central role. Our data thus point to the existence of an alternative, non-neuronal, glia-based role of CREB in plasticity.

CREB Regulates Distinct Adaptive Transcriptional Programs in Astrocytes and Neurons

“…We have previously shown that NE and FSK induce CREB-dependent transcription in astrocytes 6 ; here we confirmed that VP16-CREB does as well. Astrocytes infected with Ad2/5-CMV-VP16-CREB at MOIs of 5–30 efficiently transduced VP16-CREB, as deduced by the robust expression of VP16 mRNA and protein detected with Western blotting, immunocytochemistry and qPCR (Fig.…”

“…First, CREB-dependent transcription is activated in astrocytes by noradrenaline (NE), ATP, forskolin (FSK), tamoxifen and cinnamon 6–8 . NE and ATP act in a protein kinase C-dependent but calcium- and cyclic AMP-independent fashion, FSK activates adenylate cyclase and hence increases cyclic AMP content, whereas tamoxifen and cinnamon act via protein kinase A.…”

Targeted activation of CREB in reactive astrocytes is neuroprotective in focal acute cortical injury

“…Our study thus supports that cell type and context influence CREB actions, dispelling the widespread notion that there is a canonical CDT represented in neurons or in cell lines like HEK293. In line with this thought, we previously reported that the signaling leading to CREB activation in astrocytes is starkly different to the one documented in neurons (Carriba et al, 2012). Here we extend this observation to show that, like in neurons, the activation of CDT in astrocytes is protective-although through different mechanisms-which calls for combined therapies targeting CREB in both cells in unison.…”

“…Primary astrocyte cultures and neuronal cultures were prepared from mouse cortices as previously described (Carriba et al, 2012;Parra-Damas et al, 2014).…”

Studying Nitric Oxide in the Developing Retina: Neuromodulatory Functions and Signaling Mechanisms

“…For instance, ATP and noradrenaline may cooperate to regulate the transcription of bdnf gene in cortical astrocytes, which could directly influence activity-dependent synaptic plasticity in cortical cells [118]. Besides, it has also been shown that CREB could partially mediate a cGMP/PKG-dependent anti-apoptotic signal in R28 neuroglial progenitor cells [119], and that NO/Ca 2+ -responsive CREB signaling pathway played an important role in regulating endoplasmic reticulum-related cell death in human glioma cells [120].…”