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

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