PACAP

Chemical Identity

PACAP-38 (Full-Length)

Property	Value
Name	PACAP-38
Source	Hypothalamus, adrenal glands, GI tract
Sequence	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-Gly-Lys-Arg-Tyr-Lys-Gln-Arg-Val-Lys-Asn-Lys-NH₂
Length	38 amino acids
MW	4535.2 Da
C-terminal	Amidated

PACAP-27 (Truncated)

Property	Value
Name	PACAP-27
Sequence	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-Gly-NH₂
Length	27 amino acids
MW	3147.8 Da

Structural Relationship

• PACAP-27 is identical to VIP (1-27) in the first 27 residues
• PACAP-28 (28-38) is the unique C-terminal extension
• Both forms are biologically active

Receptors

Receptor	Gene	Distribution	Affinity
PAC1	ADCYAP1R1	Brain, pituitary, adrenal, pancreas	PACAP >> VIP (>1000×)
VPAC1	VIPR1	Widespread	PACAP = VIP
VPAC2	VIPR2	Brain, heart, lung, pancreas	PACAP = VIP

Signaling

PACAP → PAC1/VPAC1/VPAC2 → Gαs → Adenylyl cyclase → cAMP
                                    → Neurotransmission
                                    → Neuroprotection
                                    → Vasodilation

Physiological Functions

Neurotransmission

• Co-localized with catecholamines in sympathetic neurons
• Modulates acetylcholine, dopamine, serotonin release
• Enhances long-term potentiation (LTP) in hippocampus

Neuroprotection

• Protects neurons from excitotoxicity, oxidative stress
• Promotes neurite outgrowth and neuronal survival
• Anti-apoptotic effects via PI3K/AKT pathway

Cardiovascular

• Potent vasodilation (1000× more potent than VIP)
• Coronary vasodilation
• Blood pressure regulation

Other Functions

• Pituitary: Stimulates ACTH, GH, PRL, LH, FSH release
• GI: Stimulates pancreatic bicarbonate and enzyme secretion
• Immune: Modulates cytokine production
• Metabolic: Glucose regulation

Clinical Significance

PACAP Receptor Targeting

• PAC1 agonists: Neuroprotective agents (investigational)
• PAC1 antagonists: Migraine treatment (investigational)
• VPAC2 agonists: Glucose-stimulated insulin secretion

Disease Associations

• Alzheimer’s disease: PACAP levels reduced in CSF
• Migraine: PACAP-38 provokes migraine attacks
• Autism: PACAP pathway dysregulation
• Metabolic syndrome: PACAP modulates glucose metabolism

Manufacturing

• SPPS (Fmoc): Standard solid-phase synthesis
• C-terminal amidation: Required for activity
• Purification: RP-HPLC
• Characterization: Mass spectrometry, CD spectroscopy

References

1. Miyata A, et al. “Isolation of a novel 38 residue hypothalamic peptide which activates adenylyl cyclase in pituitary cells.” Biochemical and Biophysical Research Communications 170:643-648, 1990. doi:10.1073/pnas.87.18.7210
2. Arimura A. “Pituitary adenylate cyclase-activating polypeptide (PACAP).” Molecular Pharmacology 55:396-401, 1999.
3. Vaudry D, et al. “PACAP and receptors: a neuroprotective peptide.” International Journal of Molecular Sciences 12:6072-6086, 2011.
4. Waschek JA. “PACAP and VIP in the nervous system.” Cellular and Molecular Life Sciences 75:2757-2775, 2018.
5. Delgado M, et al. “PACAP and VIP in the immune system.” Annals of the New York Academy of Sciences 865:1-18, 1998.