Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP-38) Protects Cerebellar Granule Neurons from Apoptosis by Activating the Mitogen-Activated Protein Kinase (MAP Kinase) Pathway

495

462

Section: Discussionmentioning

confidence: 99%

GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism

Perry

Kindy

et al. 2009

495

462

“…These data support previous evidence in primary neuroblasts indicating a correlation between endogenous PAC1hop expression and PLC activation. Indeed, in PAC1hop expressing sympathoblasts (12,17) or immature cerebellar granule cells (36)(37)(38), PACAP increases phosphoinositide (PI) turnover and [Ca 2ϩ ] i . In contrast, the peptide does not elicit PI turnover (17) or [Ca 2ϩ ] i release (this study) in short isoform-expressing cortical precursors.…”

Section: Discussionmentioning

confidence: 99%

Regulation of neuroblast mitosis is determined by PACAP receptor isoform expression

Nicot

DiCicco‐Bloom

2001

101

Although neurogenesis in the embryo proceeds in a region-or lineage-specific fashion coincident with neuropeptide expression, a regulatory role for G protein-coupled receptors (GPCR) remains undefined. Pituitary adenylate cyclase activating polypeptide (PACAP) stimulates sympathetic neuroblast proliferation, whereas the peptide inhibits embryonic cortical precursor mitosis. Here, by using ectopic expression strategies, we show that the opposing mitogenic effects of PACAP are determined by expression of PACAP receptor splice isoforms and differential coupling to the phospholipase C (PLC) pathway, as opposed to differences in cellular context. In embryonic day 14 (E14) cortical precursors transfected with the hop receptor variant, but not cells transfected with the short variant, PACAP activates the PLC pathway, increasing intracellular calcium and eliciting translocation of protein kinase C. Ectopic expression of the hop variant in cortical neuroblasts transforms the antimitotic effect of PACAP into a promitogenic signal. Furthermore, PACAP promitogenic effects required PLC pathway function indicated by antagonist U-73122 studies in hop-transfected cortical cells and native sympathetic neuroblasts. These observations highlight the critical role of lineage-specific expression of GPCR variants in determining mitogenic signaling in neural precursors.

“…These histochemical studies suggest a functional relationship between PACAP neurons and DA and 5-HT neurons. Pharmacological studies show that PACAP has neurotrophic and neuroprotective actions on mesencephalic DA neurons (12), cortical neurons (13), cerebellar granule cells (14), and other neurons (1,2). PACAP increases tyrosine hydroxylase activity in the nucleus accumbens (15) and stimulates interleukin-6 production in astrocytes (16).…”

mentioning

confidence: 99%

Altered psychomotor behaviors in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP)

Hashimoto

Shintani²,

Tanaka³

et al. 2001

356

298

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been conserved remarkably during evolution and is widely expressed in the mammalian brain. In Drosophila, mutation of the PACAP homologue results in behavioral defects, including impaired olfaction-associated learning and changes in ethanol sensitivity. Here, we report the generation of mice lacking the PACAP gene (PACAP ؊/؊ ). PACAP ؊/؊ mice were born in the expected Mendelian ratios but had a high early-mortality rate. The surviving adult PACAP ؊/؊ mice displayed remarkable behavioral changes; they exhibited hyperactive and explosive jumping behaviors in an open field, increased exploratory behavior, and less anxiety in the elevated plus maze, emergence, and novel-object tests. Analysis of PACAP ؊/؊ mice brains revealed that the serotonin metabolite 5-hydroxyindoleacetic acid was slightly decreased in the cortex and striatum compared with wild-type mice. The present study provides evidence that PACAP plays a previously uncharacterized role in the regulation of psychomotor behaviors. P ituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasoactive intestinal peptide (VIP)͞ secretin͞glucagon family of peptides and exists in two amidated forms, PACAP38 and PACAP27, that share an identical 27-aa N terminus and are alternatively processed from a 176-aa precursor called preproPACAP (1, 2). The primary structure of PACAP38 has been conserved significantly during evolution from protochordates to mammals, suggesting that the peptide exerts important activities throughout the vertebrate phylum (1, 2). In Drosophila, recent molecular cloning and transgenic rescue experiments in the memory-mutant amnesiac, which has behavioral defects that include impaired olfaction-associated learning and changes in ethanol sensitivity, demonstrated that the amnesiac gene encodes a neuropeptide homologous to vertebrate PACAP (3, 4). In addition, mammalian PACAP activated both the cAMP and Ras͞Raf signal-transduction pathways in Drosophila neurons, suggesting a neuromodulatory role of amnesiac (Drosophila PACAP) in specific neuronal populations (5). In mammals, PACAP occurs in neuronal elements, where it acts as a pleiotropic neuropeptide via three heptahelical G protein-linked receptors-one PACAP-specific (PAC 1 ) receptor and two receptors that it shares with VIP (VPAC 1 and VPAC 2 ). PACAP stimulates several different signaling cascades in neurons, leading to the activation of adenylate cyclase, phospholipase C, and mitogen-activated protein kinase and the mobilization of calcium (1, 2, 6). Histochemical studies have shown that PACAP immunoreactivity is observed in several brain regions, including the dopamine (DA) and serotonin (5-HT) systems, with high concentrations found in the nucleus accumbens, hypothalamus, amygdala, substantia nigra, and dorsal raphe (7-9). PAC 1 receptor also is expressed throughout the target areas of both the mesocorticolimbic and nigrostriatal DA systems as well as 5-HT system (10). In addition, VPAC 1 and VPAC 2 recepto...