Decoding PACAP/VIP neuropeptide signaling reveals multiple drug targets for migraine and beyond | Research

The takeaway

PACAP and VIP signal through canonical (PAC1, VPAC1, VPAC2) and proposed (GPR55, MRGPRX2) receptors with extensive splice variant diversity, offering multiple therapeutic targets with anti-PACAP antibody already showing clinical migraine efficacy.

PACAP: the next CGRP
Anti-PACAP antibody shows clinical migraine efficacy while the complex receptor system (5+ receptors, splice variants) offers multiple targets for designer drugs

What the researchers found

PACAP/VIP: 3 canonical receptors (PAC1, VPAC1, VPAC2) + 2 proposed (GPR55, MRGPRX2). Extensive splice variant diversity. Anti-PACAP antibody: clinical migraine efficacy. Receptor signaling: membrane + endosomal. Accessory proteins modify responses. "Designer drug" opportunities.

Why it matters

With anti-PACAP antibody showing clinical migraine efficacy, understanding the full complexity of PACAP/VIP signaling enables development of more selective, effective drugs with fewer side effects.

How the study worked

Narrative review of PACAP/VIP system biology, receptor pharmacology, splice variants, and drug development opportunities.

What this study cannot tell us

Narrative review. Many receptor variants poorly characterized. Proposed non-canonical receptors need confirmation. In vivo relevance of splice variants unclear.

How to read the evidence

Comprehensive narrative review of pharmacology and drug development. Combines established and emerging evidence.

When this study was published

Published in 2025.

The bigger picture

PACAP is emerging as the next CGRP in migraine therapeutics. Unlike CGRP (one receptor), the PACAP system's multiple receptors and splice variants offer more precise drug targeting—but also greater complexity.

Questions still open

Which PAC1 splice variant is most relevant to migraine?
Could selective PAC1 variants agonists/antagonists provide migraine relief without immunosuppression?
Will GPR55 and MRGPRX2 prove to be bona fide PACAP receptors?

Common questions

What is PACAP and why is it important for migraine?

PACAP (pituitary adenylate cyclase-activating polypeptide) is a neuropeptide that, like CGRP, triggers migraine attacks when infused in patients. An antibody blocking PACAP has already shown clinical efficacy for migraine prevention, making PACAP the next major therapeutic target after CGRP.

How is PACAP different from CGRP as a drug target?

PACAP's signaling system is more complex than CGRP's—it activates at least 3 confirmed receptors (vs 1 for CGRP), each with multiple splice variants. This complexity offers more selective drug targeting opportunities but also makes drug development more challenging.

Read the original research

Decoding PACAP signaling: Splice variants, pathways and designer drugs.

Cephalalgia : an international journal of headache, 45(8), 3331024251363560

View on PubMed ↗Publisher’s paper ↗

Citation

Tasma, Zoe; Hay, Debbie L. (2025). Decoding PACAP signaling: Splice variants, pathways and designer drugs.. Cephalalgia : an international journal of headache, 45(8), 3331024251363560. https://doi.org/10.1177/03331024251363560