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Distribution and protective function of pituitary adenylate cyclase-activating polypeptide in the retina  [PDF]
Tomoya Nakamachi,Attila Matkovits,Tamotsu Seki,Seiji Shioda
Frontiers in Endocrinology , 2012, DOI: 10.3389/fendo.2012.00145
Abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP), which is found in 27- or 38-amino acid forms, belongs to the VIP/glucagon/secretin family. PACAP and its three receptor subtypes are expressed in neural tissues, with PACAP known to exert a protective effect against several types of neural damage. The retina is considered to be part of the central nervous system, and retinopathy is a common cause of profound and intractable loss of vision. This review will examine the expression and morphological distribution of PACAP and its receptors in the retina, and will summarize the current state of knowledge regarding the protective effect of PACAP against different kinds of retinal damage, such as that identified in association with diabetes, ultraviolet light, hypoxia, optic nerve transection, and toxins. This article will also address PACAP-mediated protective pathways involving retinal glial cells.
Pituitary Adenylate Cyclase Activating Peptide (PACAP) Participates in Adipogenesis by Activating ERK Signaling Pathway  [PDF]
Tatjana Arsenijevic, Fran?oise Gregoire, Jeanne Chiadak, Elodie Courtequisse, Nargis Bolaky, Jason Perret, Christine Delporte
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072607
Abstract: Pituitary adenylate cyclase activating peptide (PACAP) belongs to the secretin/glucagon/vasoactive intestinal peptide (VIP) family. Its action can be mediated by three different receptor subtypes: PAC1, which has exclusive affinity for PACAP, and VPAC1 and VPAC2 which have equal affinity for PACAP and VIP. We showed that all three receptors are expressed in 3T3-L1 cells throughout their differentiation into adipocytes. We established the activity of these receptors by cAMP accumulation upon induction by PACAP. Together with insulin and dexamethasone, PACAP induced adipogenesis in 3T3-L1 cell line. PACAP increased cAMP production within 15 min upon stimulation and targeted the expression and phosphorylation of MAPK (ERK1/2), strengthened by the ERK1/2 phosphorylation being partially or completely abolished by different combinations of PACAP receptors antagonists. We therefore speculate that ERK1/2 activation is crucial for the activation of CCAAT/enhancer- binding protein β (C/EBPβ).
Pituitary Adenylate Cyclase Activating Polypeptide Enhances Glucose-Evoked Insulin Secretion in the Canine Pancreas In Vivo
Yamaguchi N
JOP Journal of the Pancreas , 2001,
Abstract: OBJECTIVE: To study a local effect of pituitary adenylate cyclase activating polypeptide (PACAP(1-27)) on glucose-evoked insulin release under in vivo conditions. INTERVENTION: Glucose and PACAP(1-27) were locally infused to the pancreas via the superior pancreaticoduodenal artery without interrupting the blood supply. MAIN OUTCOME MEASURES: Plasma insulin and glucose concentrations were determined in samples obtained from the superior pancreaticoduodenal vein and the aorta. Superior pancreaticoduodenal venous blood flow was measured to compute the net output of insulin. RESULTS: PACAP(1-27) (0.005-5 microg) increased the basal insulin secretion by about 15 folds in a dose-dependent manner. Local infusion of either glucose (5%) or PACAP(1-27) (0.05 microg) resulted in a significant increase in the basal insulin output to about 300 microU x min(-1)g(-1), which was highly reproducible upon the second administration of the same dose with an interval of 30 min. When PACAP(1-27) was simultaneously given during glucose infusion, the increased insulin output due to glucose was further enhanced to about 600 microU x min(-1)g(-1). The net increase in PACAP(1-27)-induced insulin output in the presence of glucose was significantly greater than that obtained with PACAP(1-27) alone. There exists a strong and highly significant correlation between changes in glucose level and those in insulin output when both glucose and PACAP(1-27) were administered simultaneously. CONCLUSION: The results indicate that PACAP(1-27) directly enhances the glucose-evoked insulin secretion in the endocrine pancreas in anesthetized dogs. The study suggests that PACAP may play a local facilitating role in insulin secretion in response to glucose loading.
Pituitary Adenylate Cyclase Activating Polypeptide Modulates Catecholamine Storage and Exocytosis in PC12 Cells  [PDF]
Yan Dong, Gang Ning, Andrew G. Ewing, Michael L. Heien
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091132
Abstract: A number of efforts have been made to understand how pituitary adenylate cyclase activating polypeptide (PACAP) functions as a neurotrophic and neuroprotective factor in Parkinson’s disease (PD). Recently its effects on neurotransmission and underlying mechanisms have generated interest. In the present study, we investigate the effects of PACAP on catecholamine storage and secretion in PC12 cells with amperometry and transmission electron microscopy (TEM). PACAP increases quantal release induced by high K+ without significantly regulating the frequency of vesicle fusion events. TEM data indicate that the increased volume of the vesicle is mainly the result of enlargement of the fluidic space around the dense core. Moreover, the number of docked vesicles isn’t modulated by PACAP. When cells are acutely treated with L-DOPA, the vesicular volume and quantal release both increase dramatically. It is likely that the characteristics of amperometric spikes from L-DOPA treated cells are associated with increased volume of individual vesicles rather than a direct effect on the mechanics of exocytosis. Treatment with PACAP versus L-DOPA results in different profiles of the dynamics of exocytosis. Release via the fusion pore prior to full exocytosis was observed with the same frequency following treatment with PACAP and L-DOPA. However, release events have a shorter duration and higher average current after PACAP treatment compared to L-DOPA. Furthermore, PACAP reduced the proportion of spikes having rapid decay time and shortened the decay time of both fast and slow spikes. In contrast, the distributions of the amperometric spike decay for both fast and slow spikes were shifted to longer time following L-DOPA treatment. Compared to L-DOPA, PACAP may produce multiple favorable effects on dopaminergic neurons, including protecting dopaminergic neurons against neurodegeneration and potentially regulating dopamine storage and release, making it a promising therapeutic agent for the treatment of PD.
Comprehensive behavioral analysis of pituitary adenylate cyclase-activating polypeptide (PACAP) knockout mice  [PDF]
Keizo Takao,Koichi Tanda,Keiko Toyama,Norihito Shintani,Hitoshi Hashimoto,Tsuyoshi Miyakawa
Frontiers in Behavioral Neuroscience , 2012, DOI: 10.3389/fnbeh.2012.00058
Abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide acting as a neurotransmitter, neuromodulator, or neurotrophic factor. PACAP is widely expressed throughout the brain and exerts its functions through the PACAP-specific receptor (PAC1). Recent studies reveal that genetic variants of the PACAP and PAC1 genes are associated with mental disorders, and several behavioral abnormalities of PACAP knockout (KO) mice are reported. However, an insufficient number of backcrosses was made using PACAP KO mice on the C57BL/6J background due to their postnatal mortality. To elucidate the effects of PACAP on neuropsychiatric function, the PACAP gene was knocked out in F1 hybrid mice (C57BL/6J × 129SvEv) for appropriate control of the genetic background. The PACAP KO mice were then subjected to a behavioral test battery. PACAP deficiency had no significant effects on neurological screen. As shown previously, the mice exhibited significantly increased locomotor activity in a novel environment and abnormal anxiety-like behavior, while no obvious differences between genotypes were shown in home cage (HC) activity. In contrast to previous reports, the PACAP KO mice showed normal prepulse inhibition (PPI) and slightly decreased depression-like behavior. Previous study demonstrates that the social interaction (SI) in a resident-intruder test was decreased in PACAP KO mice. On the other hand, we showed that PACAP KO mice exhibited increased SI in Crawley's three-chamber social approach test, although PACAP KO had no significant impact on SI in a HC. PACAP KO mice also exhibited mild performance deficit in working memory in an eight-arm radial maze (RM) and the T-maze (TM), while they did not show any significant abnormalities in the left-right discrimination task in the TM. These results suggest that PACAP has an important role in the regulation of locomotor activity, social behavior, anxiety-like behavior and, potentially, working memory.
The effects of isatin (indole-2, 3-dione) on pituitary adenylate cyclase-activating polypeptide-induced hyperthermia in rats
Imre Pataki, ágnes Adamik, Vivette Glover, Gábor Tóth, Gyula Telegdy
BMC Neuroscience , 2002, DOI: 10.1186/1471-2202-3-2
Abstract: One μg intracerebroventricular (icv.) injection of PACAP-38 had hyperthermic effect in male, Wistar rats, with an onset of the effect at 2 h and a decline by the 6th h after administration. Intraperitoneal (ip.) injection of different doses of isatin (25-50 mg/kg) significantly decreased the hyperthermic effect of 1 μg PACAP-38 (icv.), whereas 12.5 mg/kg isatin (ip.) had no inhibiting effect. Isatin alone did not modify the body temperature of the animals.The mechanisms that participate in the mediation of the PACAP-38-induced hyperthermia may be modified by isatin. The capability of isatin to antagonize the hyperthermia induced by all members of the natriuretic peptide family and by PACAP-38 makes it unlikely to be acting directly on receptors for natriuretic peptides or on those for PACAP in these hyperthermic processes.Pituitary adenylate cyclase-activating polypeptide (PACAP) is known as a member of a superfamily that includes vasoactive intestinal polypeptide (VIP), secretin, glucagon, gastric inhibitory polypeptide and growth hormone-releasing factor [9]. The biologically active neuropeptide exists in two amidated forms: PACAP-38, a 38-amino-acid polypeptide; and PACAP-27, a truncated form of PACAP-38 containing 27 residues [4]. Both PACAP-38 and PACAP-27 are potent in stimulating adenylate cyclase.At least two receptor classes have been reported for PACAP in mammalian tissues: type I and type II. Type I receptors are highly selective in the recognition of PACAP, and have lower affinity for VIP. Type II receptors display similar high affinity for PACAP-27, PACAP-38 and VIP [2]. Type II (VIP-PACAP) receptors interact almost exclusively with adenylate cyclase. At least two effector systems exist for type I PACAP-preferring receptors, which can stimulate both adenylate cyclase and phospholipase C. Subsequent to phospholipase C activation via the inositol phosphate cascade, a secondary Ca2+ entry elevating cytosolic [Ca2+] follows Ca2+ mobilization [9].Recent inve
Expression and Localization of Pituitary Adenylate Cyclase-Activating Polypeptide-Specific Receptor (PAC1R) After Traumatic Brain Injury in Mice
Kentarou Morikawa, Kenji Dohi, Sachiko Yofu, Yuko Mihara, Tomoya Nakamachi, Hirokazu Ohtaki, Seiji ShiodaTohru Aruga
The Open Critical Care Medicine Journal , 2008, DOI: 10.2174/1874828700801010033]
Abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide and a well known strong neuroprotectant in various neuronal conditions. PACAP has some receptors and it acts via these receptors. PACAP type 1 receptor (PAC1R) is known as the main receptor of PACAP in neuronal damages. On the other hand, the expression and localization of PAC1R have not been elicited well in traumatic brain injury (TBI). In this study, the expression and the cellular localization of PAC1R were investigated immunohistochemically after TBI in mouse controlled cortical impact (CCI) model. The PAC1R positive cells were expressed from 3 h in the peri-contusional area and observed to 7days after the TBI. Using double-immunohistochemistry, the PAC1R immunopositive cells were co-localized with the microglia on 1day and with microglia and astrocyte on 7 days after TBI. These results suggest that PACAP and PAC1R might play an important role in traumatic brain injury as well as other conditions.
Pituitary Adenylate Cyclase-Activating Polypeptide 6-38 Blocks Cocaine- and Amphetamine-Regulated Transcript Peptide-Induced Hypophagia in Rats  [PDF]
Jonathan R. Burgos, Britt-Marie Iresj?, Ulrika Smedh
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072347
Abstract: Cocaine- and amphetamine-regulated transcript peptides (CARTp) suppress nutritional intake after administration into the fourth intracerebral ventricle. Recent in vitro studies have shown that PACAP 6-38, a pituitary adenylate cyclase-activating polypeptide (PACAP) fragment, could act as a competitive antagonist against CARTp 55-102 on a common CARTp-sensitive receptor structure. Here, we show for the first time in vivo that the reduction in solid food intake induced by exogenous CARTp 55-102 (0.3 nmol: 1.5 μg) administered fourth i.c.v. is blocked by pretreatment with PACAP 6-38 (3 nmol). The PACAP 6-38 fragment had no effect by itself either when given into the fourth ventricle or subcutaneously. Although effective to block the CARTp-effect on feeding and short-term body weight, PACAP 6-38 failed to attenuate CARTp-associated gross motor behavioral changes suggesting at least two CARTp-sensitive receptor subtypes. In conclusion, PACAP 6-38 acts as a functional CARTp antagonist in vivo and blocks its effects on feeding and short term weight gain.
Pituitary Adenylate Cyclase Activating Peptide Deficient Mice Exhibit Impaired Thymic and Extrathymic Regulatory T Cell Proliferation during EAE  [PDF]
Yossan-Var Tan, Catalina Abad, Yuqi Wang, Robert Lopez, James A. Waschek
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061200
Abstract: We have shown that mice deficient in pituitary adenylate cyclase-activating polypeptide (PACAP, gene name ADCYAP1) manifest enhanced sensitivity to experimental autoimmune encephalomyelitis (EAE), supporting the anti-inflammatory actions described for this neuropeptide. In addition to an increased proinflammatory cytokine response in these mice, a reduction in regulatory T cell (Treg) abundance in the lymph nodes (LN) was observed, suggesting altered Treg kinetics. In the present study, we compared in PACAP deficient (KO) vs. wild type mice the abundances and rates of proliferation FoxP3+ Tregs in three sites, the LN, central nervous system (CNS) and thymus and the relative proportions of Th1, Th2, and Th17 effector subsets in the LN and CNS. Flow cytometry analyses revealed a decrease in Treg proliferation and an increased T effector/Tregs ratio in the LN and CNS of PACAP KO mice. In the thymus, the primary site of do novo natural Treg production, the total numbers and proliferative rates of FoxP3+ Tregs were significantly reduced. Moreover, the expression of IL-7, a cytokine implicated in thymic Treg expansion during EAE, failed to increase at the peak of the disease in the thymus and LN of PACAP KO mice. In addition to these Treg alterations, a specific reduction of Th2 cells (about 4-fold) was observed in the lymph nodes in PACAP KO mice, with no effects on Th1 and Th17 subsets, whereas in the CNS, Th1 and Th17 cells were increased and Th2 decreased. Our results suggest that endogenous production of the neuropeptide PACAP protects against EAE by modulating Treg expansion and Th subsets at multiple sites.
Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Signalling Exerts Chondrogenesis Promoting and Protecting Effects: Implication of Calcineurin as a Downstream Target  [PDF]
Tamás Juhász, Csaba Matta, éva Katona, Csilla Somogyi, Roland Takács, Pál Gergely, László Csernoch, Gyorgy Panyi, Gábor Tóth, Dóra Regl?di, Andrea Tamás, Róza Zákány
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091541
Abstract: Pituitary adenylate cyclase activating polypeptide (PACAP) is an important neurotrophic factor influencing differentiation of neuronal elements and exerting protecting role during traumatic injuries or inflammatory processes of the central nervous system. Although increasing evidence is available on its presence and protecting function in various peripheral tissues, little is known about the role of PACAP in formation of skeletal components. To this end, we aimed to map elements of PACAP signalling in developing cartilage under physiological conditions and during oxidative stress. mRNAs of PACAP and its receptors (PAC1,VPAC1, VPAC2) were detectable during differentiation of chicken limb bud-derived chondrogenic cells in micromass cell cultures. Expression of PAC1 protein showed a peak on days of final commitment of chondrogenic cells. Administration of either the PAC1 receptor agonist PACAP 1-38, or PACAP 6-38 that is generally used as a PAC1 antagonist, augmented cartilage formation, stimulated cell proliferation and enhanced PAC1 and Sox9 protein expression. Both variants of PACAP elevated the protein expression and activity of the Ca-calmodulin dependent Ser/Thr protein phosphatase calcineurin. Application of PACAPs failed to rescue cartilage formation when the activity of calcineurin was pharmacologically inhibited with cyclosporine A. Moreover, exogenous PACAPs prevented diminishing of cartilage formation and decrease of calcineurin activity during oxidative stress. As an unexpected phenomenon, PACAP 6-38 elicited similar effects to those of PACAP 1-38, although to a different extent. On the basis of the above results, we propose calcineurin as a downstream target of PACAP signalling in differentiating chondrocytes either in normal or pathophysiological conditions. Our observations imply the therapeutical perspective that PACAP can be applied as a natural agent that may have protecting effect during joint inflammation and/or may promote cartilage regeneration during degenerative diseases of articular cartilage.
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