title: Activity-dependent neuroprotection and cAMP response element-binding protein (CREB): kinase coupling, stimulus intensity, and temporal regulation of CREB phosphorylation at serine 133.
abstract: The dual nature of the NMDA receptor as a mediator of excitotoxic cell death and activity-dependent cell survival likely results from divergent patterns of kinase activation, transcription factor activation, and gene expression. To begin to address this divergence, we examined cellular and molecular signaling events that couple excitotoxic and nontoxic levels of NMDA receptor stimulation to activation of the cAMP response element-binding protein (CREB)/cAMP response element (CRE) pathway in cultured cortical neurons. Pulses (10 min) of NMDA receptor-mediated synaptic activity (nontoxic) triggered sustained (up to 3 h) CREB phosphorylation (pCREB) at serine 133. In contrast, brief stimulation with an excitotoxic concentration of NMDA (50 microm) triggered transient pCREB. The duration of pCREB was dependent on calcineurin activity. Excitotoxic levels of NMDA stimulated calcineurin activity, whereas synaptic activity did not. Calcineurin inhibition reduced NMDA toxicity and converted the transient increase in pCREB into a sustained increase. In accordance with these observations, sustained pCREB (up to 3 h) did not require persistent kinase pathway activity. The sequence of stimulation with excitotoxic levels of NMDA and neuroprotective synaptic activity determined which stimulus exerted control over pCREB duration. Constitutively active and dominant-negative CREB constructs were used to implicate CREB in synaptic activity-dependent neuroprotection against NMDA-induced excitotoxicity. Together these data provide a framework to begin to understand how the neuroprotective and excitotoxic effects of NMDA receptor activity function in an antagonistic manner at the level of the CREB/CRE transcriptional pathway.
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Boyoung
authors.initials: B
authors.lastname: Lee
authors.forename: Greg Q
authors.initials: GQ
authors.lastname: Butcher
authors.forename: Kari R
authors.initials: KR
authors.lastname: Hoyt
authors.forename: Soren
authors.initials: S
authors.lastname: Impey
authors.forename: Karl
authors.initials: K
authors.lastname: Obrietan
mesh_terms: D000200:Action Potentials; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001640:Bicuculline / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D020013:Calcium Signaling; D000242:Cyclic AMP / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000502:physiology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D047428:Protein Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D010768:Phosphoserine; D000242:Cyclic AMP; D011494:Protein Kinases; D016559:Tacrolimus; D001640:Bicuculline