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Cognitive & Neuro · Reference monograph

Pituitary adenylate cyclase-activating polypeptide

Reference compound — not available from Purity Peptides. Shown for research context.

Overview

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide isolated in 1989 by Akira Arimura's group from ovine hypothalamus, using its ability to stimulate cAMP production in rat anterior pituitary cells as a bioassay. It exists in two amidated forms, PACAP-38 and the N-terminal fragment PACAP-27, and belongs to the secretin/glucagon/VIP superfamily, sharing substantial sequence identity with vasoactive intestinal peptide.

PACAP is widely distributed in the central and peripheral nervous systems, including trigeminal sensory neurons, parasympathetic ganglia and stress-related brain regions, and it is among the most conserved neuropeptides across vertebrates. Interest has intensified since human provocation studies showed that PACAP-38 can trigger migraine-like attacks in people with migraine, establishing the pathway as a drug target alongside CGRP. PACAP itself is not an approved medicine. It is used in research on migraine mechanisms, neuroprotection, circadian biology and stress-axis neurobiology, and as a pharmacological tool for distinguishing PAC1 from VPAC receptor function.

Mechanism studied

  1. PACAP
  2. PAC1 / VPAC receptors
  3. cAMP signalling
  4. Vasodilation & neuromodulation

PACAP acts through three class B G protein-coupled receptors. PAC1 is selective for PACAP, whereas VPAC1 and VPAC2 bind PACAP and VIP with similar affinity. All three couple strongly to Gs, raising cAMP and activating protein kinase A, and PAC1 splice variants also couple to Gq, driving phospholipase C and calcium signalling. In the trigeminovascular system, PACAP dilates meningeal arteries and promotes mast-cell degranulation, effects proposed to contribute to migraine. In neurons, PACAP signalling supports survival pathways and modulates neurotransmitter release. Receptor internalisation with sustained endosomal signalling by PAC1 has been described as a distinctive feature of this pathway.

Research highlights

  • 01Discovered in 1989 through a pituitary adenylate cyclase bioassay; PACAP-38 is the predominant tissue form.
  • 02Human provocation studies reported that PACAP-38 induces migraine-like attacks more often than VIP, despite broadly similar vasodilatory effects.
  • 03A monoclonal antibody against the PAC1 receptor did not separate from placebo in a phase 2 migraine trial, while an antibody targeting the PACAP ligand reported encouraging phase 2 results.
  • 04Genetic studies have associated variation in the PAC1 receptor gene with stress-related phenotypes, linking PACAP to stress neurobiology.
  • 05Open questions include which receptor mediates migraine effects and whether neuroprotective findings in rodent models translate to humans.

Latest published research

4,024 papers on PubMed →

  1. Regulation of PACAP gene expression by ovarian sex steroids and kisspeptin: Study using hypothalamic cell lines and an in vivo female rat model

    Tumurbaatar T et al. · Biochemistry and biophysics reports · 2026 Dec · PMID 42936012

  2. PACAP neurons of the ventral dentate gyrus are not involved in fear acquisition

    Kamalı O et al. · Physiology & behavior · 2026 Dec 1 · PMID 42722221

  3. Glyphosate alters the neurochemical phenotype of enteric neurons and modulates cytokine levels in the porcine ileum

    Palus K et al. · Toxicology letters · 2026 Nov · PMID 42767439

  4. Pituitary adenylate cyclase-activating polypeptide attenuates coronary microembolization-induced myocardial apoptosis via PAC1 receptor activation in rats

    Li L et al. · Tissue & cell · 2026 Nov · PMID 42296776

  5. Antidepressant-like activity of JZ-1201 in male rodents: a novel selective 5-HT/NE reuptake inhibitor and 5-HT(1A) receptor partial agonist

    Gao H et al. · Neuropharmacology · 2026 Nov 1 · PMID 42107524

  6. Research advances on the role of glutamate AMPA receptors in the pathogenesis and treatment of migraine: A narrative review

    Fan Y et al. · Headache · 2026 Oct 26 · PMID 42929187

  7. Differential utilization of PACAP and glutamate in parabrachial neurons shapes pain and stress responses

    Singh S et al. · bioRxiv : the preprint server for biology · 2026 Oct 11 · PMID 42926542

  8. Interictal serum L-kynurenine and PACAP-38 levels in relation to allodynia and migraine subtypes

    Durak E et al. · Headache · 2026 Oct · PMID 42312438

Live feed from PubMed (NCBI) for “PACAP”, updated 2026-10-30. Listing a paper is not an endorsement of its findings.

Registered studies

32 on ClinicalTrials.gov →

From the public ClinicalTrials.gov registry for “PACAP”, updated 2026-10-30. Shown for research context only; Purity Peptides products are not for human use.

Key references

  1. [1]Schytz et al., 2009 — Brain 132:16–25
  2. [2]PubMed — reviews on PACAP and migraine

FAQ

  • PACAP and VIP are structurally related members of the secretin/glucagon superfamily, and PACAP-27 shares roughly two-thirds of its sequence with VIP. Both activate VPAC1 and VPAC2 receptors, but only PACAP binds the PAC1 receptor with high affinity.

  • PACAP is present in trigeminal and parasympathetic neurons innervating the meninges. Experimental provocation studies found it could induce migraine-like attacks in susceptible individuals, and elevated levels have been reported during attacks. This places PACAP alongside CGRP as a neuropeptide target.

  • Both arise from the same precursor. PACAP-38 is the full-length form and is more abundant in most tissues, while PACAP-27 corresponds to its first 27 residues. They share receptor activity but differ in tissue distribution, stability and some signalling properties.

FOR RESEARCH USE ONLY.Not for human or veterinary use. Not intended to diagnose, treat, cure, or prevent any disease.

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