Pituitary adenylate cyclase-activating peptide explained

Pituitary adenylate cyclase-activating polypeptide also known as PACAP is a protein that in humans is encoded by the ADCYAP1 gene.^{[1] [2]} 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.

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.^[2]

A version of this gene has been associated with post-traumatic stress disorder (PTSD) in women (but not men).^[3] 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.^[4]

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.^{[5] [6]} 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.^{[7] [8]} Amgen's AMG-301, which targets the PAC1 receptor, failed to show greater efficacy than placebo in phase II trials.^[9]

Interactions

Pituitary adenylate cyclase-activating peptide has been shown to interact with secretin receptor.^[10]

See also

• Adenylate cyclase
• Pituitary gland

Further reading

• Book: Conconi MT, Spinazzi R, Nussdorfer GG . Endogenous ligands of PACAP/VIP receptors in the autocrine-paracrine regulation of the adrenal gland . 249 . 1–51 . 2006 . 16697281 . 10.1016/S0074-7696(06)49001-X . 978-0-12-364653-8 . International Review of Cytology .
• Cross SH, Charlton JA, Nan X, Bird AP . Purification of CpG islands using a methylated DNA binding column . Nature Genetics . 6 . 3 . 236–44 . March 1994 . 8012384 . 10.1038/ng0394-236 . 12847618 .
• Dautzenberg FM, Mevenkamp G, Wille S, Hauger RL . N-terminal splice variants of the type I PACAP receptor: isolation, characterization and ligand binding/selectivity determinants . Journal of Neuroendocrinology . 11 . 12 . 941–9 . December 1999 . 10583729 . 10.1046/j.1365-2826.1999.00411.x . 35761617 .
• Fahrenkrug J . Gut/brain peptides in the genital tract: VIP and PACAP . Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum . 61 . 234 . 35–9 . 2002 . 11713978 . 10.1080/003655101317095392 . 7249967 .
• Fahrenkrug J . PACAP--a multifacetted neuropeptide . Chronobiology International . 23 . 1–2 . 53–61 . 2006 . 16687279 . 10.1080/07420520500464569 . 29584195 .
• Felley CP, Qian JM, Mantey S, Pradhan T, Jensen RT . 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 . December 1992 . 1335692 . 10.1152/ajpgi.1992.263.6.G901 .
• Geng L, Ju G . [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 . January 1997 . 10921074 .
• Gourlet P, Vandermeers A, Robberecht P, Deschodt-Lanckman M . 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 . August 1997 . 9313778 . 10.1016/S0006-2952(97)00207-4 .
• Inagaki N, Yoshida H, Mizuta M, Mizuno N, Fujii Y, Gonoi T, Miyazaki J, Seino S . 6 . 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 . March 1994 . 8146174 . 43433 . 10.1073/pnas.91.7.2679 . 1994PNAS...91.2679I . free .
• Inooka H, Endo S, Kitada C, Mizuta E, Fujino M . 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 . November 1992 . 1483839 . 10.1111/j.1399-3011.1992.tb00324.x .
• Kimura C, Ohkubo S, Ogi K, Hosoya M, Itoh Y, Onda H, Miyata A, Jiang L, Dahl RR, Stibbs HH . 6 . 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 . January 1990 . 2302217 . 10.1016/0006-291X(90)91914-E .
• Nakata M, Yada T . PACAP in the glucose and energy homeostasis: physiological role and therapeutic potential . Current Pharmaceutical Design . 13 . 11 . 1105–12 . 2007 . 17430174 . 10.2174/138161207780618948 .
• Ohkubo S, Kimura C, Ogi K, Okazaki K, Hosoya M, Onda H, Miyata A, Arimura A, Fujino M . 6 . Primary structure and characterization of the precursor to human pituitary adenylate cyclase activating polypeptide . DNA and Cell Biology . 11 . 1 . 21–30 . 1992 . 1739432 . 10.1089/dna.1992.11.21 .
• Ohtaki T, Masuda Y, Ishibashi Y, Kitada C, Arimura A, Fujino M . Purification and characterization of the receptor for pituitary adenylate cyclase-activating polypeptide . The Journal of Biological Chemistry . 268 . 35 . 26650–7 . December 1993 . 8253796 . 10.1016/S0021-9258(19)74361-0 . free .
• Pérez-Jurado LA, Francke U . Dinucleotide repeat polymorphism at the human pituitary adenylate cyclase activating polypeptide (PACAP) gene . Human Molecular Genetics . 2 . 6 . 827 . June 1993 . 8353512 . 10.1093/hmg/2.6.827-a .
• Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BK, Hashimoto H, Galas L, Vaudry H . 6 . Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery . Pharmacological Reviews . 61 . 3 . 283–357 . September 2009 . 19805477 . 10.1124/pr.109.001370 . 5739004 .
• Waschek JA . Multiple actions of pituitary adenylyl cyclase activating peptide in nervous system development and regeneration . Developmental Neuroscience . 24 . 1 . 14–23 . 2002 . 12145407 . 10.1159/000064942 . 22281905 .
• Weber B, Riess O, Daneshvar H, Graham R, Hayden MR . (CA)n-dinucleotide repeat at the PDEB locus in 4p16.3 . Human Molecular Genetics . 2 . 6 . 827 . June 1993 . 8394765 . 10.1093/hmg/2.6.827 .
• Wray V, Kakoschke C, Nokihara K, Naruse S . Solution structure of pituitary adenylate cyclase activating polypeptide by nuclear magnetic resonance spectroscopy . Biochemistry . 32 . 22 . 5832–41 . June 1993 . 8504103 . 10.1021/bi00073a016 .
• Zeng N, Athmann C, Kang T, Lyu RM, Walsh JH, Ohning GV, Sachs G, Pisegna JR . 6 . PACAP type I receptor activation regulates ECL cells and gastric acid secretion . The Journal of Clinical Investigation . 104 . 10 . 1383–91 . November 1999 . 10562300 . 409843 . 10.1172/JCI7537 .

Notes and References

1. Hosoya M, Kimura C, Ogi K, Ohkubo S, Miyamoto Y, Kugoh H, Shimizu M, Onda H, Oshimura M, Arimura A . 6 . Structure of the human pituitary adenylate cyclase activating polypeptide (PACAP) gene . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1129 . 2 . 199–206 . January 1992 . 1730060 . 10.1016/0167-4781(92)90488-l .
2. Web site: Entrez Gene: ADCYAP1 adenylate cyclase activating polypeptide 1 (pituitary).
3. Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V . 6 . Post-traumatic stress disorder is associated with pituitary adenylate cyclase-activating polypeptide and the PAC1 receptor . Nature . 470 . 7335 . 492–7 . February 2011 . 21350482 . 3046811 . 10.1038/nature09856 . 2011Natur.470..492R .
4. Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) of the Bed Nucleus of the Stria Terminalis Mediates Heavy Alcohol Drinking in Mice. Lauren Lepeak .... eNeuro. 1 December 2023. 10 . 12 . 10.1523/ENEURO.0424-23.2023. 38053471 . free. 10755645.
5. Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M . pituitary adenylate cyclase-activating polypeptide-38 induces migraine-like attacks in patients with migraine without aura . Brain . 132 . Pt 1 . 16–25 . January 2009 . 19052139 . 10.1093/brain/awn307 . free .
6. Ghanizada H, Al-Karagholi MA, Arngrim N, Olesen J, Ashina M . PACAP27 induces migraine-like attacks in migraine patients . Cephalalgia . 40 . 1 . 57–67 . January 2020 . 31299857 . 10.1177/0333102419864507 . 196349669 .
7. Bertels Z, Pradhan AA . Emerging Treatment Targets for Migraine and Other Headaches . Headache . 59 Suppl 2 . S2 . 50–65 . July 2019 . 31291018 . 6986366 . 10.1111/head.13585 . free .
8. News: Alder BioPharmaceuticals® Announces First-in-Human Dosing in Phase 1 ALD1910 Study for Preventive Treatment of Migraine. Globenewswire News Room . GlobeNewswire. 10 October 2019. 10 October 2019.
9. Ashina M, Doležil D, Bonner JH, Zhou L, Klatt J, Picard H, Mikol DD . A phase 2, randomized, double-blind, placebo-controlled trial of AMG 301, a pituitary adenylate cyclase-activating polypeptide PAC1 receptor monoclonal antibody for migraine prevention . Cephalalgia . 41 . 1 . 33–44 . January 2021 . 33231489 . 10.1177/0333102420970889 . 7786389 .
10. Felley CP, Qian JM, Mantey S, Pradhan T, Jensen RT . 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 . December 1992 . 1335692 . 10.1152/ajpgi.1992.263.6.G901 .