PACAP Type I Receptor Activation Promotes Cerebellar Neuron Survival Through the cAMP/PKA Signaling Pathway

Abstract

The molecular nature, transduction pathways, and neurotrophic functions of pituitary adenylate cyclase activating peptide (PACAP) receptors were studied in primary culture of rat cerebellar granule cells. We show that cerebellar neurons express several PACAP type I receptor (PVR I) isoforms, including the short (PVR Is) and the Hop (PVR I-Hop) splice variants, the latter being restricted to neurons and not found in cerebellar glial cell cultures. In vitro, cerebellar granule cells die rapidly in the absence of a high concentration of K+ (25 mM), as demonstrated by TUNEL histochemistry, which shows that K+ deprivation induces massive neuronal apoptosis within 12 hr. This effect was reversed by PACAP 27 and 38. Both forms of PACAP prevent DNA fragmentation and allow long-term neuronal survival in the absence of high K+ (as shown by MAP2 immunostaining) and stimulate a reporter gene driven by the full-length c-fos promoter. These effects of PACAP are fully abolished upon transient transfection of cells with a dominant inhibitory mutant of the cAMP-dependent protein kinase (PKA). Taken together, these results show that in cerebellar granule neurons, PACAP type I receptors regulate gene expression and promote neuronal survival through the cAMP/PKA pathway.

GABABReceptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation

“…The ␣IR3 mouse monoclonal antibody against IGF-1R specifically recognizes the extracellular ␣-subunit of IGF-1R and inhibits its ligand-mediated effects (Kienlen Campard et al, 1997). We found that ␣IR3 had no effect on baclofen-induced IGF-1R phosphorylation (Fig.…”

Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death

“…Collectively, these data indicate that caspase-6 may mediate ethanol-induced activation of caspase-3. The neuroprotective effects of PACAP on granule neurons are primarily mediated through the cAMP͞protein kinase A signaling cascade (16,23,24,39). Because the inhibitory effect of PACAP on caspase-3 activity is mediated through the protein kinase A pathway (17), it is possible that inactivation of caspase-6 by PACAP can be ascribed to a protein kinase A-dependent phosphorylation (40).…”

Critical Review on the Relationship between Glaucoma and Alzheimer's Disease

“…The anti-apoptotic effects of cAMP are seen in many types of neuronal systems, including cerebellar granule neurons [164][165][166][167][168][169], dopamine neurons [170], septal cholinergic neurons [171], and sympathetic and sensory neurons [172][173][174]. A clinical study on POAG patients treated with a food supplement containing forskolin and rutin (Kronek®) has shown an improvement of the electrophysiological activity of RGC as measured by PERG analysis [175,176].…”