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 Ca2+ 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.
Highlights
A signaling is sufficient to trigger phosphorylation on cAMP response element (CRE) binding protein (CREB)’s activating serine-133 site, this is insufficient for activation of CREB-mediated gene expression
Activation of de novo gene expression has been implicated in Pituitary adenylate cyclase-activating peptide (PACAP)-mediated neuroprotection, including c-Fos, brain-derived neurotrophic factor, Bcl-2 and PACAP itself (Frechilla et al 2001; Falluel-Morel et al 2004; Shintani et al 2005; Aubert et al 2006; Dejda et al 2008). These genes are all regulated by the cAMP response element (CRE) binding protein (CREB) family of transcription factors, a group of factors that are important for the survival of central and peripheral neurons both pre- and postnatally (Walton et al 1999; Lonze et al 2002; Mantamadiotis et al 2002) and whose activation contribute to the neuroprotective effects of neurotrophins and synaptic activity (Bonni et al 1999; Riccio et al 1999; Lee et al 2005; Papadia et al 2005)
PACAP-induced CREB phosphorylation does not require action potential (AP) firing We investigated which CRE-activating molecular events triggered by PACAP treatment are reliant on activity-dependent Ca2+ signals, and whether any can be triggered in an activity-independent manner by direct protein kinase A (PKA) signaling
Summary
A signaling is sufficient to trigger phosphorylation on CREB’s activating serine-133 site, this is insufficient for activation of CREB-mediated gene expression. Activation of de novo gene expression has been implicated in PACAP-mediated neuroprotection, including c-Fos, brain-derived neurotrophic factor, Bcl-2 and PACAP itself (Frechilla et al 2001; Falluel-Morel et al 2004; Shintani et al 2005; Aubert et al 2006; Dejda et al 2008) Of note, these genes are all regulated by the cAMP response element (CRE) binding protein (CREB) family of transcription factors, a group of factors that are important for the survival of central and peripheral neurons both pre- and postnatally (Walton et al 1999; Lonze et al 2002; Mantamadiotis et al 2002) and whose activation contribute to the neuroprotective effects of neurotrophins and synaptic activity (Bonni et al 1999; Riccio et al 1999; Lee et al 2005; Papadia et al 2005). PACAP administration has been recently reported to enhance AMPAR currents as well as synaptic NMDAR currents (MacDonald et al 2007; Costa et al 2009) and to suppress the Apamininsensitive slow after-hyperpolarization (IsAHP) current (Hu et al 2011), which can control neuronal excitability
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