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. 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, 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 in women. 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, implicating this peptide and its receptor 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 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. Amgen's AMG-301, which targets the PAC1 receptor, failed to show greater efficacy than placebo in phase II trials.

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.