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Decoding PACAP signaling: Splice variants, pathways and designer drugs.
1Department of Pharmacology and Toxicology, The University of Otago, Dunedin, New Zealand.
Cephalalgia : an International Journal of Headache
|August 6, 2025
Summary
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are key in neurological signaling and linked to headaches. Understanding their complex receptor interactions offers new therapeutic targets for migraine and other headache disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are neuropeptides involved in vasodilation, immune response, and neuronal signaling.
- These peptides have been recently linked to headache disorders, particularly migraine, driving interest in their therapeutic potential.
- PACAP and VIP exert their effects through G protein-coupled receptors (GPCRs), including canonical receptors (PAC1, VPAC1, VPAC2) and potentially others (GPR55, MRGPRX2).
Purpose of the Study:
- To provide a comprehensive overview of the PACAP/VIP system, focusing on peptide, receptor, and downstream signaling mechanisms.
- To explore the complexities of PACAP/VIP receptor variants and their potential functional alterations.
- To identify potential therapeutic targets within the PACAP/VIP system for headache disorders and related conditions.
Main Methods:
- This is a narrative review, synthesizing existing research on the PACAP/VIP system.
- Literature search and analysis of studies investigating PACAP/VIP peptides, their receptors, and signaling pathways.
- Focus on studies relevant to headache disorders and drug development.
Main Results:
- The PACAP/VIP system is complex, involving multiple canonical and proposed receptors, as well as potential receptor variants.
- PACAP can activate various receptors, including PAC1, VPAC1, VPAC2, GPR55, and MRGPRX2, contributing to diverse biological actions.
- There is a limited understanding of the downstream signaling, cellular localization, and accessory protein interactions of these receptors in migraine-relevant contexts.
Conclusions:
- The intricate nature of the PACAP/VIP system presents both challenges and opportunities for drug design and validation.
- Targeting specific components of the PACAP/VIP pathway, including its receptors and signaling cascades, holds promise for novel headache disorder treatments.
- Further research into the functional mechanisms of PACAP/VIP receptors is crucial for developing effective "designer" therapeutics.
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