| Gene, mRNA, and precursor | The human preproPACAP gene, ADCYAP1, location18p11, consists of five exons. PACAP mRNAof about 3.0 kb has been detected in the human and rat bynorthern blotting analysis. Bioactive PACAP27 andPACAP38 were generated by processing with PC1 andPC2 from the precursor. The gene structure and itsmRNA size are well conserved among teleosts, amphibians, and mammals. |
| Synthesis and release | PACAP synthesis and release are stimulated by nervegrowth factor (NGF) and cAMP inducer in nervous tissues. PACAP stimulates biosynthesis by itself, indicatingthat PACAP regulates its expression level via the autocrine/paracrine system |
| Receptors | PACAP and VIP share three types of GPCRs with seventransmembrane domains: PAC1 receptor (PAC1R), andVPAC1 and VPAC2 receptors (VPAC1R, VPAC2R).PACAP binds to VPAC1R and VPAC2R with a similaraffinity to that of VIP, while PACAP interacts with PAC1Rwith 1000 times higher affinity than VIP. PAC1R has various splicing forms that differ in the presence or absence oftwo cassettes, termed HIP and HOP, in the region of thethird cytoplasmic loop (e.g., PAC1R-short, PAC1R-hop1,PAC1R-hop2, PAC1R-hip). These cassettes contribute tothe regulation of the signal transduction pathway. |
| Agonist and antagonist | Maxadilan is a specific agonist of PAC1R isolated fromthe sand fly saliva, and the modification peptide M65works as a PAC1R-specific antagonist. PACAP6–38,missing 1–5 aa residues from the N-terminal ofPACAP38, is a potential antagonist of PAC1R andVPAC2-R. VIP-6-28, missing 1–5 aa residues from theN-terminal of VIP, is a potential antagonist of VPAC1-R and VPAC2-R. |
| Biological functions | PACAP has pleiotropic functions in the central nervoussystem and peripheral tissues. PACAP acts as a neurotransmitter (neuromodulator), neuroprotectant, neuriteoutgrowth factor, and inducer of neural stem cell differentiation into astrocytes in nervous tissues. In peripheraltissues, PACAP acts as a bronchodilator, vasodilator,smooth muscle relaxant, adrenergic secretagogue in theadrenal gland, insulin secretagogue in the pancreas,inducer of spermatogenesis in testis, and immunosuppressor. PACAP also regulates the synthesis and secretion of hormones from the pituitary gland. |
| Clinical implications | PACAP may play an important role in primary headaches. The intravenous injection of PACAP inducesmigraine-like attacks in migraineurs and cluster-likeattacks in cluster headache patients, and plasma concentrations of PACAP are elevated in spontaneous attacks ofcluster headache and migraines. |
| Description | PACAP consists of 27 or 38 aa residues and belongs tothe secretin/glucagon superfamily. PACAP has pleiotropicfunctions, acting as a neurotransmitter and neurotrophic factor in the central nervous system as well as a vasodilator,insulin secretagogue, smooth muscle relaxant, and immunosuppressor in peripheral tissues. PACAP was first isolated in 1989 from the extract ofovine hypothalamus on the basis of its ability to elevatecAMP levels in rat anterior pituitary cells. |
| Uses | Pituitary adenylate cyclase activating polypeptide-38 has been used to test its effect in stimulating the formation of cyclic AMP hypothalamus and cerebral cortex slices of chicken and to treat glioblastoma cells (U87MG) in cell migration assay to test its anti-invasive effects. |
| General Description | Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) is mapped to human chromosome 18. 27-residue-amidated fragment (PACAP27) comprises another isoform. The PACAP38 is major isoform associated with mammals. |
| Biological Activity | Endogenous neuropeptide showing considerable homology with vasoactive intestinal peptide (VIP). Potently stimulates adenylyl cyclase. |
| Biochem/physiol Actions | Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) is a cardioprotectant and may help in treating radiation-induced heart disease (RIHD). It plays a protective role during oxidative stress in cardiomyocytes. PACAP38 has antioxidant, anti-apoptotic and anti-inflammatory property. It is implicated in the pathophysiology of migraine and cluster headache. |
| storage | Store at -20°C |
| Structure and conformation | PACAP38, consisting of 38 aa residues, was the firstisolated, followed by PACAP27, lacking 11 aa residuesfrom the C-terminal of PACAP38. The C-terminal of bothPACAPs was amidated. PACAP belongs to the secretin/glucagon superfamily, and its closest member is the vasoactive intestinal polypeptide (VIP), which shows 68% aasequence identity. Human PACAPs are derived from a176-aa residue precursor, located in the C-terminus, nextto the PACAP-related peptide (PRP) . ThePACAP precursor is cleaved by various prohormone convertases (PCs) to generate PACAP27 or PACAP38. Fromthe evolutionary aspect of the superfamily, the ancestralpeptide emerged about 700 million years ago, andPACAP was established by gene duplication, exon duplication, and exon deletion. The PACAP sequence is wellconserved in vertebrates, and is perfectly conserved inmammals. Stingray PACAP has 44 aa residues with two predicted processing sites, suggesting thatthe processing site of preproPACAP shows diversity inspecies. Human PACAP27, theoretical Mr 3147.6, pI 9.70;human PACAP38, theoretical Mr 4534.3, pI 10.41.PACAP is freely soluble in water and ethanol. PACAPsolution in water is unstable at 4°C, but is stable for a yearat -80°C at 0.1mM.
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