PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide) is a neuropeptide that exists in two biologically active forms: PACAP-38 (38 amino acids, MW ~4534.3 g/mol) and PACAP-27 (27 amino acids, the N-terminal fragment). PACAP-38 is the predominant form in the brain. It belongs to the VIP/secretin/glucagon superfamily and shares 68% sequence homology with VIP. PACAP is a potent neuroprotective, neurotrophic, and immunomodulatory peptide with emerging roles in migraine pathophysiology, PTSD, and neurodegenerative diseases.
Category: Neuropeptide / Reference. Evidence rating: D (animal/preclinical only).
Clinical status: Endogenous neuropeptide under active investigation. PACAP/PAC1 pathway is a validated migraine target (anti-PACAP antibody AMG 301/Lu AG09222 in Phase II). Investigated in PTSD, neurodegenerative…
PACAP signals through three receptors: PAC1 (PACAP-preferring, with >100-fold selectivity over VIP), VPAC1, and VPAC2 (shared with VIP). PAC1 couples to multiple G proteins (Gs, Gq), activating both adenylyl cyclase (cAMP/PKA) and phospholipase C (IP3/DAG/Ca2+/PKC) signaling cascades. PACAP is a…
Safety considerations: Endogenous neuropeptide — not administered therapeutically; IV PACAP-38 infusion in research settings caused headache, flushing, and palpitations in healthy volunteers and migraine patients; Potent vasodilation and mast cell activation may cause hypotension and allergic-type reactions.
Reviewed by the PeptideAtlas Editorial Team. Last reviewed: 2026-08-12.
Related peptides: Substance P, Neuropeptide Y, VIP (Vasoactive Intestinal Peptide).
Compare: PACAP vs Substance P, PACAP vs Neuropeptide Y, PACAP vs VIP (Vasoactive Intestinal Peptide).
PACAP shares 68% sequence homology with VIP and both signal through VPAC1 and VPAC2 receptors. However, PACAP also has its own preferential receptor (PAC1) with >100-fold selectivity. PACAP was discovered in 1989, nearly 20 years after VIP. They have overlapping but distinct physiological roles.
PACAP is a validated migraine trigger in human provocation studies, similar to CGRP. Anti-CGRP antibodies (erenumab, fremanezumab, galcanezumab) are proven migraine preventives. Anti-PACAP antibodies target a parallel pathway, but Phase II results have been less convincing than those for anti-CGRP drugs.
A landmark 2011 study (Ressler et al., Nature) found that PACAP blood levels and PAC1 receptor gene variants are associated with PTSD symptoms in women. This suggests the PACAP/PAC1 system may be a biomarker or therapeutic target for PTSD, though this has not yet led to approved treatments.