Pituitary adenylate cyclase-activating peptide

Pituitary adenylate cyclase-activating polypeptide also known as PACAP is a protein that in humans is encoded by the ADCYAP1 gene. pituitary adenylate cyclase-activating polypeptide is similar to vasoactive intestinal peptide. One of its effects is to stimulate enterochromaffin-like cells. It binds to vasoactive intestinal peptide receptor and to the pituitary adenylate cyclase-activating polypeptide receptor.

ADCYAP1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1GEA, 2D2P, 2JOD
Identifiers
Aliases	ADCYAP1, PACAP, adenylate cyclase activating polypeptide 1
External IDs	OMIM: 102980; MGI: 105094; HomoloGene: 869; GeneCards: ADCYAP1; OMA:ADCYAP1 - orthologs
Gene location (Human) Chr. Chromosome 18 (human) Band 18p11.32 Start 904,871 bp End 912,172 bp
Gene location (Mouse) Chr. Chromosome 17 (mouse) Band 17|17 E5 Start 93,506,445 bp End 93,513,965 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in beta cell gonad hypothalamus prefrontal cortex Brodmann area 9 gallbladder cingulate gyrus ganglionic eminence anterior cingulate cortex right frontal lobe Top expressed in lumbar spinal ganglion mammillary body ventromedial nucleus ventral tegmental area dorsomedial hypothalamic nucleus trigeminal ganglion habenula central gray substance of midbrain primary visual cortex superior frontal gyrus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function pituitary adenylate cyclase activating polypeptide activity hormone activity peptide hormone receptor binding protein binding pituitary adenylate cyclase-activating polypeptide receptor binding neuropeptide hormone activity signaling receptor binding Cellular component intracellular anatomical structure extracellular region terminal bouton extracellular space neuron projection perikaryon cell body fiber Biological process histamine secretion pituitary gland development regulation of G protein-coupled receptor signaling pathway negative regulation of glial cell proliferation female pregnancy cell-cell signaling negative regulation of cell cycle negative regulation of muscle cell apoptotic process behavioral fear response nervous system development activation of adenylate cyclase activity regulation of protein localization positive regulation of GTPase activity ATP metabolic process negative regulation of acute inflammatory response to non-antigenic stimulus regulation of oligodendrocyte progenitor proliferation cellular response to glucocorticoid stimulus positive regulation of gene expression negative regulation of GTPase activity positive regulation of synaptic transmission, glutamatergic positive regulation of chemokine (C-C motif) ligand 5 production regulation of postsynaptic membrane potential positive regulation of cell population proliferation negative regulation of potassium ion transport positive regulation of ERK1 and ERK2 cascade positive regulation of interleukin-6 production positive regulation of neuron projection development response to starvation ovarian follicle development sensory perception of pain response to ethanol negative regulation of acute inflammatory response to antigenic stimulus neuropeptide signaling pathway neuron projection development cAMP-mediated signaling positive regulation of somatostatin secretion positive regulation of transcription by RNA polymerase II positive regulation of protein kinase activity regulation of protein phosphorylation positive regulation of cytosolic calcium ion concentration insulin secretion positive regulation of growth hormone secretion regulation of signaling receptor activity G protein-coupled receptor signaling pathway adenylate cyclase-activating G protein-coupled receptor signaling pathway positive regulation of cAMP-mediated signaling brain development camera-type eye development positive regulation of cold-induced thermogenesis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 116 11516 Ensembl ENSG00000141433 ENSMUSG00000024256 UniProt P18509 O70176 RefSeq (mRNA) NM_001099733 NM_001117 NM_009625 NM_001315503 NM_001315504 RefSeq (protein) NP_001093203 NP_001108 NP_001302432 NP_001302433 NP_033755 Location (UCSC) Chr 18: 0.9 – 0.91 Mb Chr 17: 93.51 – 93.51 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Function

This gene encodes adenylate cyclase-activating polypeptide 1. Mediated by adenylate cyclase-activating polypeptide 1 receptors, this polypeptide stimulates adenylate cyclase and subsequently increases the cAMP level in target cells. Adenylate cyclase-activating polypeptide 1 not only is a hypophysiotropic hormone (i.e. a substance that induces activity in the hypophysis), but also functions as a neurotransmitter and neuromodulator. In addition, it plays a role in paracrine and autocrine regulation of certain types of cells. This gene has five exons. Exons 1 and 2 encode the 5' UTR and signal peptide, respectively; exon 4 encodes an adenylate cyclase-activating polypeptide 1-related peptide; and exon 5 encodes the mature peptide and 3' UTR. This gene encodes three different mature peptides, including two isotypes: a shorter form and a longer form.

A version of this gene has been associated with post-traumatic stress disorder (PTSD) in women (but not men). This disorder involves a maladaptive psychological response to traumatic, i.e. existence-threatening, events. Ressler et al. identified an association of a SNP in the gene coding for pituitary adenylate cyclase-activating polypeptide (PACAP), implicating this peptide and its receptor (PAC1) in PTSD. In mouse model of heavy alcohol drinking, PACAP seems to mediate alcohol effects on bed nucleus of the stria terminalis.

Headache Disorders

Both isoforms of pituitary adenylate cyclase-activating polypeptide (pituitary adenylate cyclase-activating polypeptide-38 and pituitary adenylate cyclase-activating polypeptide-27) have been implicated in migraine pathogenesis. A Danish research group led by Dr. Messoud Ashina found that intravenous infusion of pituitary adenylate cyclase-activating polypeptide-38 induced migraine attacks in 58% of people with migraine, whilst the corresponding migraine induction rate was 55% for pituitary adenylate cyclase-activating polypeptide-27. Treatments with monoclonal antibodies have been investigated to target pituitary adenylate cyclase-activating polypeptide or its receptors for the treatment of primary headache disorders. Alder BioPharmaceuticals's ALD1910, which targets the peptide, began a phase I study in October 2019. Amgen's AMG-301, which targets the PAC1 receptor, failed to show greater efficacy than placebo in phase II trials.

Interactions

Pituitary adenylate cyclase-activating peptide has been shown to interact with secretin receptor.

See also

• Adenylate cyclase
• Pituitary gland

Further reading

• Conconi MT, Spinazzi R, Nussdorfer GG (2006). Endogenous ligands of PACAP/VIP receptors in the autocrine-paracrine regulation of the adrenal gland. International Review of Cytology. Vol. 249. pp. 1–51. doi:10.1016/S0074-7696(06)49001-X. ISBN 978-0-12-364653-8. PMID 16697281.
• Cross SH, Charlton JA, Nan X, Bird AP (March 1994). "Purification of CpG islands using a methylated DNA binding column". Nature Genetics. 6 (3): 236–44. doi:10.1038/ng0394-236. PMID 8012384. S2CID 12847618.
• Dautzenberg FM, Mevenkamp G, Wille S, Hauger RL (December 1999). "N-terminal splice variants of the type I PACAP receptor: isolation, characterization and ligand binding/selectivity determinants". Journal of Neuroendocrinology. 11 (12): 941–9. doi:10.1046/j.1365-2826.1999.00411.x. PMID 10583729. S2CID 35761617.
• Fahrenkrug J (2002). "Gut/brain peptides in the genital tract: VIP and PACAP". Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum. 61 (234): 35–9. doi:10.1080/003655101317095392. PMID 11713978. S2CID 7249967.
• Fahrenkrug J (2006). "PACAP--a multifacetted neuropeptide". Chronobiology International. 23 (1–2): 53–61. doi:10.1080/07420520500464569. PMID 16687279. S2CID 29584195.
• Felley CP, Qian JM, Mantey S, Pradhan T, Jensen RT (December 1992). "Chief cells possess a receptor with high affinity for PACAP and VIP that stimulates pepsinogen release". The American Journal of Physiology. 263 (6 Pt 1): G901-7. doi:10.1152/ajpgi.1992.263.6.G901. PMID 1335692.
• Geng L, Ju G (January 1997). "[The discovery of pituitary adenylate cyclase activating polypeptide (PACAP) and its research progress]". Sheng Li Ke Xue Jin Zhan [Progress in Physiology]. 28 (1): 29–34. PMID 10921074.
• Gourlet P, Vandermeers A, Robberecht P, Deschodt-Lanckman M (August 1997). "Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP-27, but not PACAP-38) degradation by the neutral endopeptidase EC 3.4.24.11". Biochemical Pharmacology. 54 (4): 509–15. doi:10.1016/S0006-2952(97)00207-4. PMID 9313778.
• Inagaki N, Yoshida H, Mizuta M, Mizuno N, Fujii Y, Gonoi T, et al. (March 1994). "Cloning and functional characterization of a third pituitary adenylate cyclase-activating polypeptide receptor subtype expressed in insulin-secreting cells". Proceedings of the National Academy of Sciences of the United States of America. 91 (7): 2679–83. Bibcode:1994PNAS...91.2679I. doi:10.1073/pnas.91.7.2679. PMC 43433. PMID 8146174.
• Inooka H, Endo S, Kitada C, Mizuta E, Fujino M (November 1992). "Pituitary adenylate cyclase activating polypeptide (PACAP) with 27 residues. Conformation determined by 1H NMR and CD spectroscopies and distance geometry in 25% methanol solution". International Journal of Peptide and Protein Research. 40 (5): 456–64. doi:10.1111/j.1399-3011.1992.tb00324.x. PMID 1483839.
• Kimura C, Ohkubo S, Ogi K, Hosoya M, Itoh Y, Onda H, et al. (January 1990). "A novel peptide which stimulates adenylate cyclase: molecular cloning and characterization of the ovine and human cDNAs". Biochemical and Biophysical Research Communications. 166 (1): 81–9. doi:10.1016/0006-291X(90)91914-E. PMID 2302217.
• Nakata M, Yada T (2007). "PACAP in the glucose and energy homeostasis: physiological role and therapeutic potential". Current Pharmaceutical Design. 13 (11): 1105–12. doi:10.2174/138161207780618948. PMID 17430174.
• Ohkubo S, Kimura C, Ogi K, Okazaki K, Hosoya M, Onda H, et al. (1992). "Primary structure and characterization of the precursor to human pituitary adenylate cyclase activating polypeptide". DNA and Cell Biology. 11 (1): 21–30. doi:10.1089/dna.1992.11.21. PMID 1739432.
• Ohtaki T, Masuda Y, Ishibashi Y, Kitada C, Arimura A, Fujino M (December 1993). "Purification and characterization of the receptor for pituitary adenylate cyclase-activating polypeptide". The Journal of Biological Chemistry. 268 (35): 26650–7. doi:10.1016/S0021-9258(19)74361-0. PMID 8253796.
• Pérez-Jurado LA, Francke U (June 1993). "Dinucleotide repeat polymorphism at the human pituitary adenylate cyclase activating polypeptide (PACAP) gene". Human Molecular Genetics. 2 (6): 827. doi:10.1093/hmg/2.6.827-a. PMID 8353512.
• Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, et al. (September 2009). "Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery". Pharmacological Reviews. 61 (3): 283–357. doi:10.1124/pr.109.001370. PMID 19805477. S2CID 5739004.
• Waschek JA (2002). "Multiple actions of pituitary adenylyl cyclase activating peptide in nervous system development and regeneration". Developmental Neuroscience. 24 (1): 14–23. doi:10.1159/000064942. PMID 12145407. S2CID 22281905.
• Weber B, Riess O, Daneshvar H, Graham R, Hayden MR (June 1993). "(CA)n-dinucleotide repeat at the PDEB locus in 4p16.3". Human Molecular Genetics. 2 (6): 827. doi:10.1093/hmg/2.6.827. PMID 8394765.
• Wray V, Kakoschke C, Nokihara K, Naruse S (June 1993). "Solution structure of pituitary adenylate cyclase activating polypeptide by nuclear magnetic resonance spectroscopy". Biochemistry. 32 (22): 5832–41. doi:10.1021/bi00073a016. PMID 8504103.
• Zeng N, Athmann C, Kang T, Lyu RM, Walsh JH, Ohning GV, et al. (November 1999). "PACAP type I receptor activation regulates ECL cells and gastric acid secretion". The Journal of Clinical Investigation. 104 (10): 1383–91. doi:10.1172/JCI7537. PMC 409843. PMID 10562300.

External links

• Pituitary+adenylate+cyclase-activating+polypeptide at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.