Pituitary adenylate cyclase-activating peptide

{{Short description|Protein-coding gene in the species Homo sapiens}} {{cs1 config|name-list-style=vanc}} {{Infobox_gene}} '''Pituitary adenylate cyclase-activating polypeptide''', also known as '''PACAP''', is a protein that in humans is encoded by the ''ADCYAP1'' gene.<ref name="pmid1730060">{{cite journal | vauthors = Hosoya M, Kimura C, Ogi K, Ohkubo S, Miyamoto Y, Kugoh H, Shimizu M, Onda H, Oshimura M, Arimura A | display-authors = 6 | title = Structure of the human pituitary adenylate cyclase activating polypeptide (PACAP) gene | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 1129 | issue = 2 | pages = 199–206 | date = January 1992 | pmid = 1730060 | doi = 10.1016/0167-4781(92)90488-l }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ADCYAP1 adenylate cyclase activating polypeptide 1 (pituitary)| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=116}}</ref> PACAP is similar to vasoactive intestinal peptide. One of its effects is to stimulate enterochromaffin-like cells. It binds to the vasoactive intestinal peptide receptor and the PACAP 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 is not only 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.<ref name="entrez"/>

A version of this gene has been associated with post-traumatic stress disorder (PTSD) in women (but not men).<ref name="Ressler 2011">{{cite journal | vauthors = 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 | display-authors = 6 | title = Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor | journal = Nature | volume = 470 | issue = 7335 | pages = 492–7 | date = February 2011 | pmid = 21350482 | pmc = 3046811 | doi = 10.1038/nature09856 | bibcode = 2011Natur.470..492R }}</ref> 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.<ref>{{cite journal|title=Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) of the Bed Nucleus of the Stria Terminalis Mediates Heavy Alcohol Drinking in Mice|author=Lauren Lepeak ...|journal=eNeuro|date=1 December 2023|volume=10 |issue=12 |doi=10.1523/ENEURO.0424-23.2023|pmid=38053471 |doi-access=free|pmc=10755645}}</ref>

===Headache Disorders=== Both isoforms of PACAP (PACAP-38 and PACAP-27) have been implicated in migraine pathogenesis.<ref name=":0">{{cite journal | vauthors = Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M | title = PACAP38 induces migraine-like attacks in patients with migraine without aura | journal = Brain | volume = 132 | issue = Pt 1 | pages = 16–25 | date = January 2009 | pmid = 19052139 | doi = 10.1093/brain/awn307 | doi-access = free }}</ref><ref name=":1">{{cite journal | vauthors = Ghanizada H, Al-Karagholi MA, Arngrim N, Olesen J, Ashina M | title = PACAP27 induces migraine-like attacks in migraine patients | journal = Cephalalgia | volume = 40 | issue = 1 | pages = 57–67 | date = January 2020 | pmid = 31299857 | doi = 10.1177/0333102419864507 | s2cid = 196349669 }}</ref> A Danish research group led by Dr. Messoud Ashina found that intravenous infusion of PACAP-38 induced migraine attacks in 58% of people with migraine,<ref name=":0" /> whilst the corresponding migraine induction rate was 55% for PACAP-27.<ref name=":1" /> Treatments with monoclonal antibodies have been investigated to target PACAP or its receptors for the treatment of primary headache disorders. In a phase 2, proof of concept study published in 2024, a monoclonal antibody treatment targeting PACAP (denoted Lu AG09222) reduced the number of migraine days in patients suffering from treatment-resistant migraines.<ref name="Ashina2024">{{cite journal | vauthors = Ashina M, Phul R, Khodaie M, Löf E, Florea I | title = A Monoclonal Antibody to PACAP for Migraine Prevention | journal = N Engl J Med | volume = 391 | issue = 9 | pages = 800-809 | date = September 2024 | doi = 10.1056/NEJMoa2314577 | url= https://www.nejm.org/doi/full/10.1056/NEJMoa2314577 }}</ref> Attempts to target its receptors have been less successful. Amgen's AMG-301, which targets the PAC1 receptor, failed to show greater efficacy than placebo in phase II trials.<ref name="AshinaDoležil2020">{{cite journal | vauthors = Ashina M, Doležil D, Bonner JH, Zhou L, Klatt J, Picard H, Mikol DD | title = 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 | journal = Cephalalgia | volume = 41 | issue = 1 | pages = 33–44 | date = January 2021 | pmid = 33231489 | doi = 10.1177/0333102420970889 | pmc = 7786389 }}</ref>

===Neuroprotective=== PACAP has also been shown to be neuroprotective, though its tendency to induce migraines has limited clinical use of this property.<ref>{{cite journal | title=Central neuropeptides as key modulators of astrocyte function in neurodegenerative and neuropsychiatric disorders | journal=Psychopharmacology | date=2025 | doi=10.1007/s00213-025-06840-9 | pmid=40536717 | vauthors = Yang M, Jia M, Cai M, Feng X, Huang L, Yang J | doi-access=free | pmc=12578712 }}</ref><ref>{{cite journal | title=More Than Three Decades After Discovery of the Neuroprotective Effect of PACAP, What is Still Preventing Its Clinical Use? | journal=Journal of Molecular Neuroscience | date=2025 | volume=75 | issue=3 | article-number=80 | doi=10.1007/s12031-025-02366-z | pmid=40542938 | vauthors = Cherait A, Xifró X, Reglodi D, Vaudry D | pmc=12182478 }}</ref>

== Interactions ==

Pituitary adenylate cyclase-activating peptide has been shown to interact with the secretin receptor (with low affinity),<ref name=pmid1335692>{{cite journal | vauthors = Felley CP, Qian JM, Mantey S, Pradhan T, Jensen RT | title = Chief cells possess a receptor with high affinity for PACAP and VIP that stimulates pepsinogen release | journal = The American Journal of Physiology | volume = 263 | issue = 6 Pt 1 | pages = G901-7 | date = December 1992 | pmid = 1335692 | doi = 10.1152/ajpgi.1992.263.6.G901 }}</ref> as well as MRGPRX2<ref>{{cite journal | title=Decoding PACAP signaling: Splice variants, pathways and designer drugs | journal=Cephalalgia | date=2025 | volume=45 | issue=8 | article-number=03331024251363560 | doi=10.1177/03331024251363560 | pmid=40767099 | vauthors = Tasma Z, Hay DL | doi-access=free }}</ref> and GPR55.<ref>{{cite journal | title=Gene Expression Data Mining Reveals the Involvement of GPR55 and Its Endogenous Ligands in Immune Response, Cancer, and Differentiation | journal=International Journal of Molecular Sciences | date=2021 | volume=22 | issue=24 | article-number=13328 | doi=10.3390/ijms222413328 | pmid=34948125 | doi-access=free | vauthors = Wnorowski A, Wójcik J, Maj M | pmc=8707311 }}</ref>

== See also == * Adenylate cyclase * Pituitary gland

== References == {{reflist}}

== Further reading == {{refbegin | 2}} * {{cite book | vauthors = Conconi MT, Spinazzi R, Nussdorfer GG | title = Endogenous Ligands of PACAP/VIP Receptors in the Autocrine–Paracrine Regulation of the Adrenal Gland | volume = 249 | pages = 1–51 | year = 2006 | pmid = 16697281 | doi = 10.1016/S0074-7696(06)49001-X | isbn = 978-0-12-364653-8 | series = International Review of Cytology }} * {{cite journal | vauthors = Cross SH, Charlton JA, Nan X, Bird AP | title = Purification of CpG islands using a methylated DNA binding column | journal = Nature Genetics | volume = 6 | issue = 3 | pages = 236–44 | date = March 1994 | pmid = 8012384 | doi = 10.1038/ng0394-236 | s2cid = 12847618 }} * {{cite journal | vauthors = Dautzenberg FM, Mevenkamp G, Wille S, Hauger RL | title = N-terminal splice variants of the type I PACAP receptor: isolation, characterization and ligand binding/selectivity determinants | journal = Journal of Neuroendocrinology | volume = 11 | issue = 12 | pages = 941–9 | date = December 1999 | pmid = 10583729 | doi = 10.1046/j.1365-2826.1999.00411.x | s2cid = 35761617 }} * {{cite journal | vauthors = Fahrenkrug J | title = Gut/brain peptides in the genital tract: VIP and PACAP | journal = Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum | volume = 61 | issue = 234 | pages = 35–9 | year = 2002 | pmid = 11713978 | doi = 10.1080/003655101317095392 | s2cid = 7249967 }} * {{cite journal | vauthors = Fahrenkrug J | title = PACAP--a multifacetted neuropeptide | journal = Chronobiology International | volume = 23 | issue = 1–2 | pages = 53–61 | year = 2006 | pmid = 16687279 | doi = 10.1080/07420520500464569 | s2cid = 29584195 }} * {{cite journal | vauthors = Felley CP, Qian JM, Mantey S, Pradhan T, Jensen RT | title = Chief cells possess a receptor with high affinity for PACAP and VIP that stimulates pepsinogen release | journal = The American Journal of Physiology | volume = 263 | issue = 6 Pt 1 | pages = G901-7 | date = December 1992 | pmid = 1335692 | doi = 10.1152/ajpgi.1992.263.6.G901 }} * {{cite journal | vauthors = Geng L, Ju G | title = [The discovery of pituitary adenylate cyclase activating polypeptide (PACAP) and its research progress] | journal = Sheng Li Ke Xue Jin Zhan [Progress in Physiology] | volume = 28 | issue = 1 | pages = 29–34 | date = January 1997 | pmid = 10921074 }} * {{cite journal | vauthors = Gourlet P, Vandermeers A, Robberecht P, Deschodt-Lanckman M | title = 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 | journal = Biochemical Pharmacology | volume = 54 | issue = 4 | pages = 509–15 | date = August 1997 | pmid = 9313778 | doi = 10.1016/S0006-2952(97)00207-4 }} * {{cite journal | vauthors = Inagaki N, Yoshida H, Mizuta M, Mizuno N, Fujii Y, Gonoi T, Miyazaki J, Seino S | display-authors = 6 | title = Cloning and functional characterization of a third pituitary adenylate cyclase-activating polypeptide receptor subtype expressed in insulin-secreting cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 7 | pages = 2679–83 | date = March 1994 | pmid = 8146174 | pmc = 43433 | doi = 10.1073/pnas.91.7.2679 | bibcode = 1994PNAS...91.2679I | doi-access = free }} * {{cite journal | vauthors = Inooka H, Endo S, Kitada C, Mizuta E, Fujino M | title = Pituitary adenylate cyclase activating polypeptide (PACAP) with 27 residues. Conformation determined by 1H NMR and CD spectroscopies and distance geometry in 25% methanol solution | journal = International Journal of Peptide and Protein Research | volume = 40 | issue = 5 | pages = 456–64 | date = November 1992 | pmid = 1483839 | doi = 10.1111/j.1399-3011.1992.tb00324.x }} * {{cite journal | vauthors = Kimura C, Ohkubo S, Ogi K, Hosoya M, Itoh Y, Onda H, Miyata A, Jiang L, Dahl RR, Stibbs HH | display-authors = 6 | title = A novel peptide which stimulates adenylate cyclase: molecular cloning and characterization of the ovine and human cDNAs | journal = Biochemical and Biophysical Research Communications | volume = 166 | issue = 1 | pages = 81–9 | date = January 1990 | pmid = 2302217 | doi = 10.1016/0006-291X(90)91914-E | bibcode = 1990BBRC..166...81K }} * {{cite journal | vauthors = Nakata M, Yada T | title = PACAP in the glucose and energy homeostasis: physiological role and therapeutic potential | journal = Current Pharmaceutical Design | volume = 13 | issue = 11 | pages = 1105–12 | year = 2007 | pmid = 17430174 | doi = 10.2174/138161207780618948 }} * {{cite journal | vauthors = Ohkubo S, Kimura C, Ogi K, Okazaki K, Hosoya M, Onda H, Miyata A, Arimura A, Fujino M | display-authors = 6 | title = Primary structure and characterization of the precursor to human pituitary adenylate cyclase activating polypeptide | journal = DNA and Cell Biology | volume = 11 | issue = 1 | pages = 21–30 | year = 1992 | pmid = 1739432 | doi = 10.1089/dna.1992.11.21 }} * {{cite journal | vauthors = Ohtaki T, Masuda Y, Ishibashi Y, Kitada C, Arimura A, Fujino M | title = Purification and characterization of the receptor for pituitary adenylate cyclase-activating polypeptide | journal = The Journal of Biological Chemistry | volume = 268 | issue = 35 | pages = 26650–7 | date = December 1993 | pmid = 8253796 | doi = 10.1016/S0021-9258(19)74361-0 | doi-access = free }} * {{cite journal | vauthors = Pérez-Jurado LA, Francke U | title = Dinucleotide repeat polymorphism at the human pituitary adenylate cyclase activating polypeptide (PACAP) gene | journal = Human Molecular Genetics | volume = 2 | issue = 6 | page = 827 | date = June 1993 | pmid = 8353512 | doi = 10.1093/hmg/2.6.827-a }} * {{cite journal | vauthors = Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BK, Hashimoto H, Galas L, Vaudry H | display-authors = 6 | title = Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery | journal = Pharmacological Reviews | volume = 61 | issue = 3 | pages = 283–357 | date = September 2009 | pmid = 19805477 | doi = 10.1124/pr.109.001370 | s2cid = 5739004 }} * {{cite journal | vauthors = Waschek JA | title = Multiple actions of pituitary adenylyl cyclase activating peptide in nervous system development and regeneration | journal = Developmental Neuroscience | volume = 24 | issue = 1 | pages = 14–23 | year = 2002 | pmid = 12145407 | doi = 10.1159/000064942 | s2cid = 22281905 }} * {{cite journal | vauthors = Weber B, Riess O, Daneshvar H, Graham R, Hayden MR | title = (CA)n-dinucleotide repeat at the PDEB locus in 4p16.3 | journal = Human Molecular Genetics | volume = 2 | issue = 6 | page = 827 | date = June 1993 | pmid = 8394765 | doi = 10.1093/hmg/2.6.827 }} * {{cite journal | vauthors = Wray V, Kakoschke C, Nokihara K, Naruse S | title = Solution structure of pituitary adenylate cyclase activating polypeptide by nuclear magnetic resonance spectroscopy | journal = Biochemistry | volume = 32 | issue = 22 | pages = 5832–41 | date = June 1993 | pmid = 8504103 | doi = 10.1021/bi00073a016 }} * {{cite journal | vauthors = Zeng N, Athmann C, Kang T, Lyu RM, Walsh JH, Ohning GV, Sachs G, Pisegna JR | display-authors = 6 | title = PACAP type I receptor activation regulates ECL cells and gastric acid secretion | journal = The Journal of Clinical Investigation | volume = 104 | issue = 10 | pages = 1383–91 | date = November 1999 | pmid = 10562300 | pmc = 409843 | doi = 10.1172/JCI7537 }} {{refend}}

== External links == * {{MeshName|Pituitary+adenylate+cyclase-activating+polypeptide}}

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Category:Genes on human chromosome 18