Disease relevance of MGC29506

• In four of the neuroblastoma cell lines, VIP and PACAP stimulated cyclic AMP production with different potencies and levels of maximal stimulation [1].
• Pituitary adenylate cyclase-activating peptide 38 (PACAP 38) is a neuropeptide that displays several biological effects of interest in the context of airway diseases such as asthma and chronic obstructive pulmonary disease [2].
• Co-treatment with neutralizing antiserum to RANTES attenuated PACAP-mediated protection from toxicity associated with gp120 [3].
• Since this year, using three models of disease, septic shock, rheumathoid arthritis, and Crohn's disease, we are trying to contribute with new pieces to the puzzle of immunity to approach the use of VIP/PACAP system as a therapeutic agent [4].
• The effect of PACAP 38 administration on neuroendocrine and immune parameters was examined in rats with LPS-induced peritonitis [5].

Psychiatry related information on MGC29506

• However, PACAP effectively ameliorated behavioral symptoms in all groups, with a degree of recovery depending on age and endocrine status [6].

High impact information on MGC29506

• In this issue of the JCI, Lang et al. demonstrate that overexpression of the pituitary adenylate cyclase-activating polypeptide (PACAP) type I (PAC1) receptor gene results in abnormal development of the SCO and vel cells, leading to congenital hydrocephalus (see the related article beginning on page 1924) [7].
• Here we report the cloning, by the yeast two hybrid system with dominant negative caspase-2 as "bait," of a proapoptotic molecule named proapoptotic caspase adaptor protein (PACAP), encoded by a 372-base pair open reading frame [8].
• Northern blot analysis revealed gene expression for only the PACAP-preferring (PAC1) receptor [9].
• Consistent with this notion, we determined that the most BrdU positive NPCs differentiated to astrocytes through PAC1 signaling [10].
• It has been well established that the PACAP/PAC1 system induces differentiation of neural progenitor cells (NPCs) through the Gs-mediated cAMP-dependent signaling pathway [10].

Chemical compound and disease context of MGC29506

• MGC29506 gene, frequently down-regulated in intestinal-type gastric cancer, encodes secreted-type protein with conserved cysteine residues [11].
• Contrasting effects of PACAP and carbachol on [Ca2+]i and inositol phosphates in human neuroblastoma NB-OK-1 cells [12].
• Human A-type ANP receptor upregulation by PACAP and carbachol in neuroblastoma cells [13].
• We have previously shown that PACAP ameliorates the neurological symptoms and reduces the dopaminergic cell loss in young male rats, in a 6-hydroxydopamine (6-OHDA)-induced lesion of the substantia nigra, a model of Parkinson's disease [6].
• Reduction in the activity of PMNs to respond to PACAP was observed after cell exposure to inhibitors of the cAMP/protein kinase A (PKA), protein kinase C (PKC), and PI3K pathways, to pertussis toxin (PTX), genistein, and after chelation of intracellular calcium or after extracellular calcium depletion [14].

Biological context of MGC29506

• MGC29506 and PACAP were derived from the same gene, consisting of four exons, due to alternative splicing of alternative splice-acceptor-site type [11].
• Fourteen human ESTs were the MGC29506 type, while one human EST was the PACAP type [11].
• A standard 48 well chemotaxis chamber was used to assess the effects of PACAP on N-Formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced neutrophil chemotaxis and spontaneous random migration [2].
• MGC29506 was the major isoform of the MGC29506/PACAP gene on human chromosome 5q31 [11].
• Alternative splicing of two exons occurs in human and rat PAC1 gene generating splice variants with variable tissue-specific expression [15].

Anatomical context of MGC29506

• Activation of the cAMP/protein kinase A pathway in Caco-2 cell monolayers either using pharmacological tools (forskolin, 8-br-cAMP, [(11,22,28)Ala]VIP) or physiological activators (the neuropeptides VIP and PACAP) inhibited hPAT1 function (beta-alanine uptake) at the apical membrane [16].
• We report that in freshly isolated human monocytes PACAP acts as a pro-inflammatory molecule [17].
• Likewise, high numbers of NOS- and PACAP-containing nerve cell bodies were seen in both ganglia [18].
• Our research about VIP/PACAP and the immune system goes back to 1990 when our group described the expression of VIP on lymphocytes for the first time [4].
• These data demonstrate that chVIP, PACAP, and to a lesser extent helodermin were capable of potently stimulating cAMP generation in the avian central nervous system [19].

Associations of MGC29506 with chemical compounds

• At 37 degrees C PACAP transiently increased cAMP levels in the presence of the non-specific phosphodiesterase inhibitor IBMX, suggesting rapid desensitization [20].
• The differential effects of PACAP peptides on SCG NPY and catecholamine content and secretion coincided with previous studies that activated directly the sympathetic intracellular cyclic AMP-protein kinase A signaling pathway [21].
• This is accompanied by a dramatic switch in the expression of receptors for the structurally related neuropeptides VIP (vasoactive intestinal polypeptide) and PACAP (pituitary adenylate cyclase activating polypeptide) [22].
• When administered together with LPS, PACAP 38 reversed its effect on immune and humoral parameters, causing a decrease in the serum concentrations of TNFalpha and corticosterone, and an increase in T4 and GH [5].
• Dopamine (100 microM), PACAP (50 nM) and forskolin (10 microM) induced a 50-, 30- and 40-fold cAMP accumulation on glial cells, respectively, but not ip3 production [23].

Regulatory relationships of MGC29506

• Administration of the beta-adrenoreceptor agonist isoproterenol mimicked the stimulatory effect of PACAP on both steroid secretion whereas preincubation of fetal cells with the beta-adrenoreceptor antagonist propranolol suppressed the steroidogenic effect of PACAP [24].

Other interactions of MGC29506

• In this study, the GHRH/PACAP cDNA was cloned from grouper hypothalamic tissue [25].
• The neuropeptide pituitary adenylate cyclase-activating protein (PACAP) acts via the G protein-coupled receptor vasoactive intestinal peptide (VIP)/PACAP receptor-1 to induce phospholipase C (PLC)/calcium and mitogen-activated protein kinase (MAPK)-dependent proinflammatory activities in human polymorphonuclear neutrophils (PMNs) [14].
• Human PACAP response gene 1 (p22/PRG1): proliferation-associated expression in pancreatic carcinoma cells [26].
• Here we show, using in situ hybridization and immunohistochemistry, that melanopsin, a recently identified opsin, is expressed in retinal ganglion cells which also co-store PACAP, a neurotransmitter of the RHT [27].
• Homologous desensitization with nanomoles of PACAP concentration and heterologous receptors desensibilization by G protein-coupled receptor agonists were observed [14].

Analytical, diagnostic and therapeutic context of MGC29506

• In situ hybridization showed that the PAC1 receptor gene was expressed highly in the pallium, preoptic nucleus, and nucleus of cerebellum, and moderately in the Purkinje cell layer of the cerebellum [28].
• Sequence analysis of the human PCR-amplified PAC1 variant was therefore carried out and revealed that human placenta only expresses the PAC1SV2 isoform [15].
• Both the long and the short forms of the GHRH/PACAP precursor cDNA were identified in grouper 22 issues as well as expression in embryos and larvae by semi-quantitative RT-PCR detection [25].
• RESULTS: PACAP and PAC(1)-R were localized by immunohistochemistry in the prostate tissue [29].
• PACAP (10 pmol kg(-1) min(-1)) or placebo (0.9% saline) was infused for 20 min into 12 healthy young volunteers in a cross over, double blind study. rCBF was measured with SPECT and (133)Xe inhalation and mean blood flow velocity in the middle cerebral artery was measured with transcranial Doppler ultrasonography [30].

References