Pituitary adenylate cyclase-activating peptide

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.

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 PACAP (PACAP-38 and PACAP-27) have been implicated in migraine pathogenesis. 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, whilst the corresponding migraine induction rate was 55% for PACAP-27. Treatments with monoclonal antibodies have been investigated to target PACAP 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.{{cite news|title=Alder BioPharmaceuticals® Announces First-in-Human Dosing in Phase 1 ALD1910 Study for Preventive Treatment of Migraine|newspaper=Globenewswire News Room |publisher=GlobeNewswire|date=10 October 2019|url=https://www.globenewswire.com/news-release/2019/10/10/1927997/0/en/Alder-BioPharmaceuticals-Announces-First-in-Human-Dosing-in-Phase-1-ALD1910-Study-for-Preventive-Treatment-of-Migraine.html|access-date=10 October 2019

Neuroprotective

PACAP has also been shown to be neuroprotective, though its tendency to induce migraines has limited clinical use of this property.

Interactions

Pituitary adenylate cyclase-activating peptide has been shown to interact with secretin receptor, as well as MRGPRX2 and GPR55.

References

References

1. (January 1992). "Structure of the human pituitary adenylate cyclase activating polypeptide (PACAP) gene". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression.
2. "Entrez Gene: ADCYAP1 adenylate cyclase activating polypeptide 1 (pituitary)".
3. (February 2011). "Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor". Nature.
4. Lauren Lepeak .... (1 December 2023). "Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) of the Bed Nucleus of the Stria Terminalis Mediates Heavy Alcohol Drinking in Mice". eNeuro.
5. (January 2009). "PACAP38 induces migraine-like attacks in patients with migraine without aura". Brain.
6. (January 2020). "PACAP27 induces migraine-like attacks in migraine patients". Cephalalgia.
7. (July 2019). "Emerging Treatment Targets for Migraine and Other Headaches". Headache.
8. (January 2021). "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.
9. (2025). "Central neuropeptides as key modulators of astrocyte function in neurodegenerative and neuropsychiatric disorders". Psychopharmacology.
10. (2025). "More Than Three Decades After Discovery of the Neuroprotective Effect of PACAP, What is Still Preventing Its Clinical Use?". Journal of Molecular Neuroscience.
11. (December 1992). "Chief cells possess a receptor with high affinity for PACAP and VIP that stimulates pepsinogen release". The American Journal of Physiology.
12. (2025). "Decoding PACAP signaling: Splice variants, pathways and designer drugs". Cephalalgia.
13. (2021). "Gene Expression Data Mining Reveals the Involvement of GPR55 and Its Endogenous Ligands in Immune Response, Cancer, and Differentiation". International Journal of Molecular Sciences.