Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are structurally related neuropeptides belonging to the secretin/glucagon superfamily. Both activate VPAC receptors with similar affinity but diverge at the PAC1 receptor, where PACAP acts selectively. This receptor selectivity creates distinct physiological profiles despite 68% sequence homology.
- Sequence: 28 amino acids (HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH₂)
- MW: 3,326 Da
- pI: ~10.5
- Structure: Amphipathic α-helix
- Discovery: Said and Mutt in 1970
- Distribution: CNS, gut, pancreas, cardiovascular system
Two bioactive forms exist:
- PACAP-38: 38 amino acids (full-length, primary form)
- PACAP-27: N-terminal 27 amino acids (conserved with VIP)
- Sequence homology with VIP: 68% in first 27 residues
- MW: 4,530 Da (PACAP-38)
- Discovery: Miyata in 1989
- Distribution: CNS, pituitary, adrenal medulla, testis
Both VIP and PACAP bind VPAC receptors with similar affinity:
| Receptor | VIP EC₅₀ | PACAP EC₅₀ | Tissue Distribution |
|---|
| VPAC1 | ~1 nM | ~1 nM | Pancreas, lung, liver, CNS |
| VPAC2 | ~1 nM | ~1 nM | Brain, heart, pancreas, GI tract |
VPAC receptor activation stimulates adenylyl cyclase → cAMP → PKA, producing:
- Vasodilation
- Bronchodilation
- Hormone secretion
- Immune modulation
The PAC1 receptor is highly selective for PACAP over VIP:
| Receptor | PACAP EC₅₀ | VIP EC₅₀ | Selectivity Ratio |
|---|
| PAC1 | ~1 nM | >1 µM | >1000:1 (PACAP-selective) |
PAC1 receptor activation stimulates:
- Phospholipase C → IP3/DAG → calcium mobilization
- Adenylyl cyclase (in some splice variants)
- Neuronal differentiation
- Neurotransmitter release
| System | Effect | Mechanism |
|---|
| Cardiovascular | Vasodilation, hypotension | cAMP → smooth muscle relaxation |
| Respiratory | Bronchodilation | Airway smooth muscle relaxation |
| Gastrointestinal | Fluid secretion, relaxation | Crypt cell secretion, motility |
| Endocrine | Insulin, glucagon release | Pancreatic islet stimulation |
| Immune | Immunomodulation | T cell, macrophage activation |
| Neurotransmission | Slow EPSP | CNS neurotransmitter |
| System | Effect | Mechanism |
|---|
| Neuroendocrine | ACTH, GH, catecholamine release | Pituitary and adrenal stimulation |
| Neurotransmission | Fast EPSP, neuromodulation | Calcium-dependent neurotransmitter release |
| Neuroprotection | Neuronal survival | cAMP/CREB pathway |
| Development | Neural crest migration | Cytoskeletal regulation |
| Immune | Mast cell degranulation | PAC1 on mast cells |
| Cardiovascular | Vasodilation (shared with VIP) | VPAC-mediated |
- Highest concentration: GI tract (enteric neurons)
- CNS: Cortex, hippocampus, hypothalamus
- Cardiovascular: Heart, blood vessels
- Immune: Lymphoid tissues
- Highest concentration: Hypothalamus, pituitary
- CNS: Widespread (higher than VIP in brain)
- Peripheral: Adrenal medulla, testis, pancreas
- Immune: Mast cells, macrophages
| Application | Mechanism | Status |
|---|
| Erectile dysfunction | Vasodilation | Approved (Invicorp) |
| Pulmonary hypertension | Pulmonary vasodilation | Investigational |
| Cerebral vasospasm | Cerebral vasodilation | Investigational |
| Asthma | Bronchodilation | Investigational |
| VIPoma syndrome | Diagnostic marker | Clinical use |
| Application | Mechanism | Status |
|---|
| Migraine | CGRP pathway modulation | Investigational |
| Neurodegeneration | Neuroprotection | Preclinical |
| Type 2 diabetes | Incretin-like effects | Investigational |
| PTSD | Fear extinction, anxiolysis | Investigational |
| Growth hormone deficiency | GH stimulation | Investigational |
| Parameter | VIP | PACAP-38 |
|---|
| Half-life (plasma) | 1–2 minutes | 2–5 minutes |
| Metabolism | DPP-IV, NEP | DPP-IV, NEP |
| Stable analogs | Yes (VIP analogue) | Yes (PACAP analogs) |
| Oral bioavailability | None | None |
| CNS penetration | Limited | Limited |
Both peptides are rapidly degraded by peptidases, necessitating engineered analogs for therapeutic use.
| Analog | Modification | Half-life | Selectivity |
|---|
| [R15,20,21,L27]-VIP | Multiple substitutions | ~30 min | VPAC-selective |
| Stearyl-VIP | Fatty acid acylation | ~2 hours | VPAC1/VPAC2 |
| Ro 25-1553 | N-terminal modification | ~1 hour | VPAC2-selective |
| Analog | Modification | Half-life | Selectivity |
|---|
| PACAP 1-38 amide | C-terminal amidation | ~10 min | PAC1 + VPAC |
| [Ala16]-PACAP | Ala substitution | ~30 min | PAC1-selective |
| Maxadilan | Maxillary shark peptide | ~1 hour | PAC1-selective |
| Side Effect | Incidence | Mechanism |
|---|
| Flushing | 30–50% | Systemic vasodilation |
| Hypotension | 20–30% | Vasodilation |
| Diarrhea | 20–30% | GI secretion |
| Bronchospasm | 10–20% | Paradoxical in asthma |
| Headache | 10–15% | Cerebral vasodilation |
| Side Effect | Incidence | Mechanism |
|---|
| Flushing | 20–40% | Vasodilation |
| Hypotension | 10–20% | Vasodilation |
| Tachycardia | 10–20% | Reflex response |
| Facial flushing | 30–50% | Cutaneous vasodilation |
| Nausea | 10–15% | GI effects |
| Feature | VIP | PACAP |
|---|
| Size | 28 aa | 38 aa (or 27 aa) |
| MW | 3,326 Da | 4,530 Da |
| Sequence homology | 68% (with PACAP-27) | 68% (with VIP) |
| VPAC1/VPAC2 binding | High | High |
| PAC1 binding | None | High (>1000× selectivity) |
| Primary function | Vasodilation, secretion | Neuroprotection, secretion |
| Neurotransmitter | Slow EPSP | Fast EPSP |
| Stable analogs | Yes | Yes |
| Therapeutic stage | Approved (ED) | Investigational |
The key distinction is PACAP’s selective activation of PAC1 receptors, which mediates neuroprotective, neurodevelopmental, and neuroendocrine functions absent from VIP pharmacology. This makes PACAP a candidate for neurodegenerative diseases, PTSD, and metabolic disorders where VIP’s vasodilatory profile is less relevant.
- Said SI, Mutt V. “Potent peripheral and splanchnic vasodilation peptide from porcine intestine.” Proc Natl Acad Sci 1970;67:706-713.
- Miyata A, et al. “PACAP: a novel pituitary adenylate cyclase-activating polypeptide.” Biochem Biophys Res Commun 1989;166:581-589.
- Vaudry D, et al. “Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions.” Pharmacol Rev 2000;52:269-324.
- Harmar AJ, et al. “VPAC receptors and VIP.” Pharmacol Rev 1998;50:265-299.
- Waschek JA. “VIP and PACAP: neuropeptide modulators of neural injury, repair, and adaptation.” Am J Physiol 2013;304:G535-G544.
