title: Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1.
abstract: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuroprotective peptide which exerts its effects mainly through the cAMP-protein kinase A (PKA) pathway. Here, we show that in cortical neurons, PACAP-induced PKA signaling exerts a major part of its neuroprotective effects indirectly, by triggering action potential (AP) firing. Treatment of cortical neurons with PACAP induces a rapid and sustained PKA-dependent increase in AP firing and associated intracellular Ca(2+) transients, which are essential for the anti-apoptotic actions of PACAP. Transient exposure to PACAP induces long-lasting neuroprotection in the face of apoptotic insults which is reliant on AP firing and the activation of cAMP response element (CRE) binding protein (CREB)-mediated gene expression. Although direct, activity-independent PKA signaling is sufficient to trigger phosphorylation on CREB's activating serine-133 site, this is insufficient for activation of CREB-mediated gene expression. Full activation is dependent on CREB-regulated transcription co-activator 1 (CRTC1), whose PACAP-induced nuclear import is dependent on firing activity-dependent calcineurin signaling. Over-expression of CRTC1 is sufficient to rescue PACAP-induced CRE-mediated gene expression in the face of activity-blockade, while dominant negative CRTC1 interferes with PACAP-induced, CREB-mediated neuroprotection. Thus, the enhancement of AP firing may play a significant role in the neuroprotective actions of PACAP and other adenylate cyclase-coupled ligands.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Baxter
authors.forename: Marc-Andre
authors.initials: MA
authors.lastname: Martel
authors.forename: Aoife
authors.initials: A
authors.lastname: McMahon
authors.forename: Peter C
authors.initials: PC
authors.lastname: Kind
authors.forename: Giles E
authors.initials: GE
authors.lastname: Hardingham
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D019703:Calcineurin / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D003470:Culture Media; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D055724:Electrophysiological Phenomena; D018696:Neuroprotective Agents; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D019311:Staurosporine / Q000037:antagonists & inhibitors / Q000633:toxicity; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection
chemical_list: C519510:Crtc1 protein, rat; D003470:Culture Media; D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014157:Transcription Factors; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D019311:Staurosporine; D002118:Calcium