Vasoactive intestinal peptide, usually shortened to VIP, is a 28-residue neuropeptide that turns up almost everywhere physiologists look: in gut nerves, airway nerves, the brain’s master circadian clock and activated immune cells. It was first purified as a substance that widened blood vessels, and five decades later it is still a standard tool for probing cAMP signaling through class B G protein-coupled receptors.
The sections below trace where VIP came from, how its two main receptors work, and which research areas lean on it most heavily. Each section points to primary papers or major reviews, and a short section at the end sets out what the literature has not established.
At a glance
- Class: Neuropeptide of the secretin/glucagon family; closest relative is PACAP
- Discovery: Isolated from porcine small intestine by Sami Said and Viktor Mutt, reported in 1970
- Structure: 28 amino acids, amidated C-terminus; C147H237N43O43S; MW 3326.8 g/mol; CAS 37221-79-7
- Main research areas: smooth-muscle and vascular physiology, intestinal secretion, neuroimmunology, circadian biology, pulmonary vascular biology
- Regulatory status: Not an FDA-approved drug; sold here as a research reagent only
Structure and origin
Said and Mutt were screening tissue extracts for vasoactive material when they isolated a basic polypeptide from hog small intestine that lowered blood pressure and relaxed smooth muscle in several preparations (Said & Mutt, 1970). Its full amino acid sequence was worked out a few years later, and it proved to be closely related to secretin and glucagon. Human and porcine VIP share the same sequence.
Structurally, VIP has three features that matter in the lab. The C-terminal asparagine is amidated, which is needed for full receptor activity. A single methionine at position 17 is prone to oxidation, which is one reason the peptide must be kept dry and cold. And the molecule is a substrate for several peptidases, so native VIP has a very short life in biological fluids. That instability has driven decades of work on cyclized, lipidated and receptor-selective analogs. The discovery of pituitary adenylate cyclase-activating polypeptide (PACAP) in 1989 added a second ligand with about two-thirds sequence identity to VIP in its first 28 residues.
Mechanism: what the research shows
VIP binds two receptors, VPAC1 and VPAC2, with similarly high affinity, and it shares both with PACAP. A third receptor, PAC1, strongly prefers PACAP. All three belong to the class B (secretin-like) GPCR family, with a large N-terminal extracellular domain that captures the peptide’s C-terminal helix while the N-terminus engages the transmembrane core (Harmar et al., 2012).
The dominant signal from both VPAC receptors is Gs coupling, adenylyl cyclase activation and a rise in intracellular cAMP, followed by protein kinase A activity. Coupling to Gq and calcium mobilization has also been reported in some cell types. VPAC1 is abundant in liver, lung, intestine and T lymphocytes, while VPAC2 is prominent in smooth muscle, pancreas and the suprachiasmatic nucleus. Most of the receptor pharmacology comes from transfected CHO and HEK293 cell lines, radioligand binding and cAMP accumulation assays, and from knockout mice lacking VIP or one of the receptors (Harmar et al., 2012).
Key areas of study
Smooth muscle and the vasculature
The original 1970 report described relaxation of vascular and other smooth muscle, and organ-bath work with isolated arteries, trachea and gut segments remains a core use of the peptide (Said & Mutt, 1970). In the pulmonary circulation, male mice lacking the VIP gene developed moderate pulmonary arterial hypertension with remodeling of small pulmonary arteries, and the authors reported that these changes were attenuated when VIP was given in the model (Said et al., 2007). That study made VIP-knockout mice a reference model for VIP signaling in lung vessels.
Neuroimmunology
Macrophages, dendritic cells and T cells express VPAC receptors, and lymphocytes themselves can produce VIP. A detailed review from Delgado, Pozo and Ganea summarized cell-culture and rodent work showing that VIP reduced production of proinflammatory mediators such as TNF-α, IL-6, IL-12 and nitric oxide by activated macrophages, shifted T-cell responses away from the Th1 profile, and was associated with less tissue damage in rodent models of arthritis, colitis and endotoxic shock (Delgado et al., 2004). These findings positioned VIP as a model “neuroimmune” peptide linking nerve signals to immune cell behavior.
Circadian biology
In the suprachiasmatic nucleus, a subset of neurons releases VIP onto neighbors that carry VPAC2. Mice lacking VPAC2 could not sustain normal circadian rhythms of behavior in constant darkness, and their suprachiasmatic neurons lost coordinated rhythmic firing and clock-gene expression (Harmar et al., 2002). That result identified VIP-to-VPAC2 signaling as a key synchronizing signal among clock cells, and VIP and VPAC2 knockout lines are now standard tools in chronobiology.
Receptor pharmacology and analog design
Because VIP and PACAP act at overlapping receptors, much effort has gone into selective agonists and antagonists for VPAC1, VPAC2 and PAC1. The IUPHAR review of this receptor family lists the main tool ligands, their selectivity and the phenotypes of each knockout line, and it remains the standard reference for nomenclature (Harmar et al., 2012).
What the evidence does not show
Much of the VIP literature is mechanistic work in cell lines, isolated tissues and knockout mice. Anti-inflammatory effects seen in rodent models depend on the model, timing and route used, and they do not establish any effect outside those settings. The peptide’s rapid enzymatic breakdown also complicates interpretation: an effect seen in an organ bath may not occur when the peptide meets plasma peptidases. VIP also acts at several receptors in many tissues at once, so attributing an effect to one receptor usually requires selective ligands or knockout animals. Synthetic VIP has been evaluated in clinical studies, but none of that work describes the research material sold here.
Regulatory status
VIP is not an FDA-approved drug in the United States. Synthetic VIP has been evaluated in clinical studies. The material offered by Rogue Compounds is a research reagent only and is not for human or veterinary use.
Handling and storage in the lab
Lyophilized VIP should be kept sealed and refrigerated at 2–8°C (36–46°F), protected from light. Keeping the vial closed until use limits exposure to moisture and air, which matters for a peptide with an oxidation-prone methionine.
Sourcing and documentation
Rogue Compounds has VIP made in small batches. Every vial carries a batch number and a QR code that opens the independent U.S. testing lab’s own report for that batch. The same batch COA is posted on the product page and in the COA Library.
References
- Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169(3951):1217-1218. PMID 5450698
- Harmar AJ, et al. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharmacol. 2012;166(1):4-17. PMID 22289055
- Delgado M, Pozo D, Ganea D. The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev. 2004;56(2):249-290. PMID 15169929
- Harmar AJ, et al. The VPAC2 receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell. 2002;109(4):497-508. PMID 12086606
- Said SI, et al. Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene. Circulation. 2007;115(10):1260-1268. PMID 17309917
Research use only. Rogue Compounds products are sold strictly for laboratory research. They are not for human or veterinary use, and nothing in this article is medical advice. The studies cited here describe published research, not this product or any use of it.