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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
Author(s) -
Baxter Paul S.,
Martel MarcAndre,
McMahon Aoife,
Kind Peter C.,
Hardingham Giles E.
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07330.x
Subject(s) - creb , neuroprotection , cyclic amp response element binding protein , adenylate kinase , activator (genetics) , pituitary adenylate cyclase activating peptide , microbiology and biotechnology , signal transduction , protein kinase a , chemistry , transcription factor , biology , phosphorylation , vasoactive intestinal peptide , receptor , neuropeptide , neuroscience , biochemistry , gene
J. Neurochem. (2011) 118 , 365–378. 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.