A signaling cascade of nuclear calcium-CREB-ATF3 activated by synaptic NMDA receptors defines a gene repression module that protects against extrasynaptic NMDA receptor-induced neuronal cell death and ischemic brain damage

• Verfasst von: Zhang, Sheng-Jia [VerfasserIn]
• Verfasst von: Buchthal, Bettina [VerfasserIn]
• Verfasst von: Lau, David [VerfasserIn]
• Verfasst von: Hayer, Stefanie Nicole [VerfasserIn]
• Verfasst von: Dick, Oliver [VerfasserIn]
• Verfasst von: Schwaninger, Markus [VerfasserIn]
• Verfasst von: Veltkamp, Roland [VerfasserIn]
• Verfasst von: Zou, Ming [VerfasserIn]
• Verfasst von: Weiss, Ursula [VerfasserIn]
• Verfasst von: Bading, Hilmar [VerfasserIn]
• Titel: A signaling cascade of nuclear calcium-CREB-ATF3 activated by synaptic NMDA receptors defines a gene repression module that protects against extrasynaptic NMDA receptor-induced neuronal cell death and ischemic brain damage
• Verf.angabe: Sheng-Jia Zhang, Bettina Buchthal, David Lau, Stefanie Hayer, Oliver Dick, Markus Schwaninger, Roland Veltkamp, Ming Zou, Ursula Weiss, and Hilmar Bading
• E-Jahr: 2011
• Jahr: March 30, 2011
• Umfang: 13 S.
• Fussnoten: Gesehen am 16.01.2023
• Titel Quelle: Enthalten in: The journal of neuroscience
• Ort Quelle: Washington, DC : Soc., 1981
• Jahr Quelle: 2011
• Band/Heft Quelle: 31(2011), 13, Seite 4978-4990
• ISSN Quelle: 1529-2401
• DOI: doi:10.1523/JNEUROSCI.2672-10.2011
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1831146096

Abstract

Synapse-to-nucleus signaling triggered by synaptic NMDA receptors can lead to the buildup of a neuroprotective shield. Nuclear calcium activating the cAMP response element binding protein (CREB) plays a key role in neuroprotection acquired by synaptic activity. Here we show that in mouse hippocampal neurons, the transcription factor Atf3 (activating transcription factor 3) is a direct target of CREB. Induction of ATF3 expression by CREB in hippocampal neurons was initiated by calcium entry through synaptic NMDA receptors and required nuclear calcium transients and calcium/calmodulin-dependent protein kinase IV activity. Acting as a transcriptional repressor, ATF3 protects cultured hippocampal neurons from apoptosis and extrasynaptic NMDA receptor-induced cell death triggered by bath application of NMDA or oxygen-glucose deprivation. Expression of ATF3 in vivo using stereotaxic delivery of recombinant adeno-associated virus reduces brain damage following a cerebral ischemic insult in mice. Conversion of ATF3 to a transcriptional activator transforms ATF3 into a potent prodeath protein that kills neurons in cell culture and, when expressed in vivo in the hippocampus, ablates the neuronal cell layer. These results link nuclear calcium-CREB signaling to an ATF3-mediated neuroprotective gene repression program, indicating that activity-dependent shutoff of genes is an important process for survival. ATF3 supplementation may counteract age- and disease-related neuronal cell loss caused by a reduction in synaptic activity, malfunctioning of calcium signaling toward and within the nucleus (“nuclear calciopathy”), or increases in death signaling by extrasynaptic NMDA receptors.