Page data last changed: . Registry refreshes and identity assessments are separate from scientific content review.
VIP's closest relative, present as 38- and 27-residue forms, and the neuropeptide now being chased as the next migraine target after CGRP.
Also known as: Pituitary adenylate cyclase-activating polypeptide · PACAP-38 · PACAP-27
Part of the Neuropeptides & signaling cluster
Overview
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide of the VIP/secretin/glucagon superfamily that exists as PACAP-38 and PACAP-27 and binds three G-protein-coupled receptors, PAC1, VPAC1 and VPAC2. It is expressed throughout the nervous system, with high levels in the hypothalamus, and is studied in feeding, stress, reproduction, neuroprotection and — most actively — migraine, where it has emerged as a therapeutic target alongside CGRP.
Source & context
Biological / chemical source: Hypothalamus and central/peripheral nervous system (human, mouse, rat and sheep PACAP-27 are identical)
Primary research or clinical context: Endogenous neuropeptide; not a medicine — an emerging drug target in migraine, where antibodies against PACAP are being developed
What PACAP is
Pituitary adenylate cyclase-activating polypeptide “belongs to the vasoactive intestinal polypeptide (VIP)/secretin/glucagon superfamily. PACAP is present in two forms (PACAP-38 and PACAP-27) and binds to three guanine-regulatory (G) protein-coupled receptors (PAC1, VPAC1, and VPAC2)” (Sureshkumar et al., Brain Sciences 2021). It was “originally isolated as a hypothalamic peptide” and “has a widespread distribution in the body and has a diverse spectrum of actions” (Koppan et al., Frontiers in Endocrinology 2022). The IUPHAR Guide to Pharmacology records PACAP-27 as HSDGIFTDSYSRYRKQMAVKKYLAAVL with a C-terminal leucine amide, and notes that the human, mouse, rat and sheep sequences of PACAP-27 are identical — an unusual degree of conservation that reflects how old and essential the peptide is.
Two forms, three receptors
PACAP-38 and PACAP-27 come from the same precursor; the shorter form is the N-terminal 27 residues of the longer one, and both are amidated. The PAC1 receptor prefers PACAP over VIP by orders of magnitude, whereas VPAC1 and VPAC2 bind both peptides similarly, which is why PACAP shares many of VIP's actions on smooth muscle and secretion but has its own neuronal signature through PAC1. A structure–function study using conformationally restricted analogues identified PAC1-selective agonists (Ramos-Álvarez et al., Peptides 2015), the kind of tool needed to separate PACAP's receptor-specific effects. The VIP profile on this site covers the shared receptors in detail.
| Detail | |
|---|---|
| PACAP-38 | 38 residues, amidated; the predominant form |
| PACAP-27 | N-terminal 27 residues of PACAP-38, amidated; sequence identical in human, mouse, rat, sheep |
| PAC1 | PACAP-selective receptor |
| VPAC1 / VPAC2 | Shared with VIP |
What it does
The literature in the evidence pack spans several systems. PACAP “is expressed in the central and peripheral nervous systems, with high PACAP levels found in the hypothalamus, a brain region involved in feeding and energy homeostasis,” and the PACAP/PAC1 system regulates feeding (Sureshkumar et al. 2021). It orchestrates stress-related responses in neural circuits (Boucher et al., Peptides 2021) and shows functional heterogeneity across stress, learning and pathology (Rajbhandari et al., Neurobiology of Learning and Memory 2023). It is “a regulator of mammalian reproductive function” (Winters and Moore, Molecular and Cellular Endocrinology 2020) with specific female reproductive roles (Koppan et al. 2022), has protective effects in ischaemia (Reglodi et al., Journal of Headache and Pain 2018), and PACAP deficiency has been proposed as a model of ageing (Reglodi et al., GeroScience 2018).
Migraine: the next target after CGRP
The most active translational thread is headache. “The most studied peptide is calcitonin gene-related peptide (CGRP), which is a well-established migraine trigger and therapeutic target. Recently, another peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), has emerged as an alternative target for migraine therapeutics” (Pietra et al., Cephalalgia 2025). PACAP's role in primary headaches was reviewed in 2018 (Edvinsson et al., Journal of Headache and Pain 2018). The ClinicalTrials.gov snapshot for September 2026 lists 31 registered studies naming PACAP, including trials that induce migraine attacks with the peptide and measure PACAP-38 as a biomarker after interventional procedures. The strategy, as with CGRP, is to block the peptide or its receptor, not to give it.
Relation to other peptides on this site
PACAP is VIP's closest relative — the two share the VPAC receptors — and both sit in the secretin/glucagon superfamily with GLP-1, glucagon, GIP, secretin and GHRH, all of which act on class B receptors. Its migraine story parallels CGRP, which has its own profile. For readers of the growth-hormone and metabolic clusters, PACAP is a reminder that the same receptor architecture that incretin drugs exploit runs through the nervous system with entirely different physiology.
Regulatory status
PACAP is an endogenous neuropeptide and a laboratory reagent; no PACAP product is approved as a medicine, and the therapeutic programmes in migraine target the peptide rather than administer it. This profile is educational and is not guidance on obtaining or using any product.
Sequence of the selected reference form
Sequence backbone for the reference form: Human PACAP27, Leu27-amide free peptide. Termini, stereochemistry and modifications are described below.
Structure & chemistry
Molecular identity & reference confidence
Source-supported reference
Reviewed UniProt independently defines humanPACAP27 and its Leu-amide. PubChem91935802 supplies the same all-L backbone, including defined Ile/Thr side-chain stereochemistry, and terminal amide withC142H224N40O39S/3147.6. PACAP38 is a separate isoform and no PACAP38 identifiers are imported. It encodes38residues HSDGIFTDSYSRYRKQMAVKKYLAAVLGKGYKQRVKNK, including Gly30 rather than Arg30 of reviewed humanPACAP38. It is neither the selected27-residue form nor exact reviewed humanPACAP38. These share the PACAP27 connectivity but have unspecified stereochemistry (standard InChIKeyRZGBUJXSKLDAFE-UHFFFAOYSA-N). The exact all-L PACAP27 CID91935802 hasRZGBUJXSKLDAFE-QYHUGZLJSA-N and matches reviewed UniProt.
- Molecular form
- Human PACAP27, Leu27-amide free peptide
- Species
- Homo sapiens
- Termini (N / C)
- Free His amino terminus / Leu carboxamide
Average reference mass · Molecular identity assessment: 2026-10-05
Reference policy updated: 2026-10-05
- PubChem PUG molecular properties, CID 91935802 · 2026-10-05
- PubChem structure-derived biologic notation, CID 91935802 · 2026-10-05
- Reviewed UniProtKB P18509 · 2026-10-05
- PubChem structure-derived biologic notation, CID 133082079 · 2026-10-05
H-His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu-NH2
- Molecular formula
- C142H224N40O39S
- Average reference mass
- ≈ 3,147.6
- Receptors
- PAC1 (PACAP-selective), VPAC1 and VPAC2 (shared with VIP) — class B G-protein-coupled receptors coupled to adenylate cyclase
- Backbone
- Human PACAP27, Leu27-amide free peptide
- C-terminus
- Leu carboxamide
- Status
- Endogenous neuropeptide; not a medicine — drug target in migraine as of September 2026
- PubChem CID: 91935802
Chemistry values: curated profile, PubChem.
Clinical development snapshot
ClinicalTrials.gov lists 32 registered studies with “PACAP” as an intervention (snapshot 2026-10-01). A registry footprint is not evidence of efficacy or approval.
| NCT | Title | Phase | Status | Updated |
|---|---|---|---|---|
| NCT07832032 | Biological Profiles of Neuropeptides, Neurotrophins and miRNA in Migraine | — | not yet recruiting | 2026-09-21 |
| NCT07690696 | Tear Biomarkers for Migraine | — | not yet recruiting | 2026-07-10 |
| NCT07395908 | The Effect of Interventional Procedures on Serum CGRP and PACAP-38 Levels in Chronic Migraine | Not applicable | active not recruiting | 2026-02-09 |
| NCT07342296 | Induction of Migraine Attacks With Aura Using Pituitary Adenylate Cyclase Activating Polypeptide-38 | Not applicable | not yet recruiting | 2026-01-15 |
| NCT06573502 | Platelet Rich Plasma Combined With Platelet Rich Fibrin in Management of Temporomandibular Joint Osteoarthriti | Not applicable | completed | 2025-12-12 |
| NCT06018025 | NDPH Biomarker Study in Children and Adolescents | — | completed | 2025-12-01 |
PACAP — reconstitution calculator
Enter how much peptide is in the vial and how much diluent (e.g. bacteriostatic water) is added. The tool returns the resulting solution concentration — and, for any amount you type, the volume it corresponds to. This is educational arithmetic, not a dosing recommendation.
Reference form: Human PACAP27, Leu27-amide free peptideAverage reference mass: 3,147.6 Da
Enter an amount to see the volume it corresponds to.
Educational concentration mathematics only. This tool does not recommend a dose, amount, or protocol, and nothing here is medical advice. Many peptides are not authorized by Health Canada for human use — see our reconstitution and bacteriostatic-water guides for context.
Change log
Dated observations from the data pipeline (registry flags, trial footprints, identifiers) and editorial reviews of this profile.
- ChemistryPubChem formula updated to C199H322N60O53S.
- Trials1 registered study added on ClinicalTrials.gov (now 32).
- IdentifiersCross-linked to IUPHAR ligand 2257 and PubChem CID 16133238.
- TrialsClinicalTrials.gov snapshot added: 31 registered studies, highest phase 4.
- EditorialProfile content reviewed and updated by the editorial team.
FAQ about PACAP
What is PACAP?+
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide of the VIP/secretin/glucagon superfamily that exists as PACAP-38 and PACAP-27 and binds three G-protein-coupled receptors, PAC1, VPAC1 and VPAC2. It is expressed throughout the nervous system, with high levels in the hypothalamus, and is studied in feeding, stress, reproduction, neuroprotection and — most actively — migraine, where it has emerged as a therapeutic target alongside CGRP.
What Canadian product status is recorded for PACAP?+
Canadian product status for PACAP has not been verified in this profile. No verified record here does not mean no authorization exists. Status depends on the product, formulation and use; consult Health Canada's product records.
What is the length of the selected reference form for PACAP?+
The selected reference form (Human PACAP27, Leu27-amide free peptide) has 27 residues or residue-derived units in its backbone. Other forms in this family may have a different length.
What is PACAP?+
Pituitary adenylate cyclase-activating polypeptide, a neuropeptide of the VIP/secretin/glucagon superfamily present as 38- and 27-residue forms. It binds PAC1, VPAC1 and VPAC2 receptors and is involved in feeding, stress, reproduction, neuroprotection and migraine.
What is the difference between PACAP-38 and PACAP-27?+
PACAP-27 is the N-terminal 27 residues of PACAP-38; both are amidated and come from the same precursor. PACAP-38 is the predominant form.
Why is PACAP studied in migraine?+
It can trigger migraine-like attacks and has emerged as a therapeutic target alongside CGRP; treatments in development block the peptide or its receptor.
How is PACAP related to VIP?+
They are close relatives in the same superfamily and share the VPAC1 and VPAC2 receptors; PAC1 is PACAP-selective.
Is PACAP a drug?+
No. It is an endogenous peptide and research reagent; the drug candidates are antibodies or antagonists against it.
Related peptides
References & further reading
- 1.Pietra et al. (2025). PACAP versus CGRP in migraine: From mouse models to clinical translation. Cephalalgia
- 2.Sureshkumar et al. (2021). The PACAP/PAC1 Receptor System and Feeding. Brain Sciences
- 3.Ramos-Álvarez et al. (2015). A structure-function study of PACAP using conformationally restricted analogs: Identification of PAC1 receptor-selective PACAP agonists. Peptides
- 4.Edvinsson et al. (2018). PACAP and its role in primary headaches. Journal of Headache and Pain
- 5.Reglodi et al. (2018). Protective effects of PACAP in ischemia. Journal of Headache and Pain
- 6.Boucher et al. (2021). PACAP orchestration of stress-related responses in neural circuits. Peptides
- 7.Winters & Moore (2020). PACAP: A regulator of mammalian reproductive function. Molecular and Cellular Endocrinology
- 8.PubChem — PACAP-27 (CID 16133238)