ADCYAP1 gene

The ADCYAP1 gene (ADCYAP1 stands for: adenylate cyclase-activating polypeptide 1) is a protein-coding gene located on chromosome 18p11.32. The ADCYAP1 gene encodes a secreted proprotein that is proteolytically processed into several mature peptides (PACAP). PACAP, a neuropeptide, exists in two bioactive forms PACAP27 and PACAP38, which differ by eleven amino acid residues in the C-terminus. These peptides stimulate adenylate cyclase and increase cyclic adenosine monophosphate (cAMP) levels, leading to transcriptional activation of target genes. The encoded products of the ADCYAP1 gene are important mediators of neuroendocrine stress responses. Alternative splicing leads to several transcript variants. PACAP is similar to the "vasoactive intestinal peptide (VIP)".

As a neuropeptide, PACAP is involved in a variety of physiological processes and binds to various receptors. It binds to various receptors, including both the VIP receptor and its specific PACAP receptor (Inooka H et al. 2001; Emery AC et al. 2013). PACAP exerts neuroprotective and general cytoprotective effects due to its anti-apoptotic, anti-inflammatory and antioxidant activity (Emery AC et al. 2013). Promotes the development of neuronal projections via the RAPGEF2/Rap1/B-Raf/ERK signaling pathway (Emery AC et al. 2013). PACAP Induces a long-lasting increase in intracellular calcium concentrations and neuroendocrine secretion in chromaffin cells. Involved in the control of glucose homeostasis and induces insulin secretion by pancreatic beta cells.

Neuroprotective: PACAP also showed neuroprotective properties, however its tendency to trigger migraine limited the clinical use of this property (Ghanizada H et al. 2020). The pituitary adenylate cyclase-activating peptide has been shown to interact with the secretin receptor (Tasma Z et al. 2025).

Diseases associated with ADCYAP1 include ASIA (also known as Gulf War syndrome or Gulf War Illness or Chronic Multi-symptom Illness) and sudden infant death syndrome.

1. Ghanizada H et al. (2020) PACAP27 induces migraine-like attacks in migraine patients. Cephalalgia 40:57-67.
2. Inooka H et al. (2001) Conformation of a peptide ligand bound to its G-protein coupled receptor. Nat Struct Biol 8:161-165.
3. Emery AC et al. (2013) Rapgef2 connects GPCR-mediated cAMP signals to ERK activation in neuronal and endocrine cells. Sci Signal 6 (281):ra51.
4. Piper SJ et al. (2022) Understanding VPAC receptor family peptide binding and selectivity. Nat Commun 13:7013.
5. Tasma Z et al. (2025) Decoding PACAP signaling: Splice variants, pathways and designer drugs. Cephalalgia 45:3331024251363560.
6. Wang J et al. (2020) Cryo-EM structures of PAC1 receptor reveal ligand binding mechanism. Cell Res 30:436-445.