What Is VIP (Vasoactive Intestinal Peptide)? Structure, Receptor Signalling and Research Uses

Vasoactive intestinal peptide (VIP) is a neuropeptide of 28 amino acids with an amidated C-terminus, belonging to the secretin-glucagon superfamily. It acts on two G protein-coupled receptors, VPAC1 and VPAC2, and its principal signal is a rise in intracellular cAMP. Researchers first purified it from pig intestine in the early 1970s because it dilated blood vessels, but it soon proved to be present well outside the digestive tract — in central and peripheral neurons, in the respiratory tree, throughout the gut wall and in immune tissue. That wide distribution explains why one peptide surfaces in fields as far apart as chronobiology, lung physiology and immunology.

Below we describe where VIP comes from and how it is built, how it engages its receptors, which research questions it is used to address, and the practical side of working with it — vial sizes, concentration calculations, stability and what to look for on a certificate. The peptide is supplied lyophilized.

Discovery and molecular structure

Sami Said and Viktor Mutt purified VIP from porcine duodenum while systematically screening intestinal extracts for vasoactive compounds, so the name reflects how it was found rather than what it chiefly does — VIP is not, in the main, a gut hormone. It is encoded by the VIP gene, whose precursor also gives rise to the related peptide PHM (called PHI in some species), and it is produced by neurons rather than a conventional endocrine gland, acting as a neurotransmitter and local paracrine signal.

Two structural characteristics define VIP. The first is its family. It shares much of its sequence with PACAP, secretin, glucagon and GHRH; all of these fold into a similar helix and activate class B GPCRs by a two-step mechanism in which the peptide's C-terminal half docks onto the receptor's large extracellular domain, after which the N-terminal residues reach into the transmembrane bundle and switch on signalling. This division of labour has a direct practical consequence: fragments missing the N-terminus still bind but no longer activate, which is exactly how antagonists within this family are designed.

The second characteristic is amidation at the C-terminus. Native VIP ends in asparagine amide rather than a free carboxylic acid, a post-translational change carried out by peptidylglycine alpha-amidating monooxygenase. The amide removes the negative charge at the chain end and is needed for full receptor activation, so a free-acid peptide with the same sequence is effectively a different compound. Laboratories sourcing VIP should verify that the amide is present — the difference between products is real and has consequences for results.

Mechanism of action

VIP binds VPAC1 and VPAC2 with broadly similar affinity, and both receptors signal mainly through Gs. Activation stimulates adenylyl cyclase, elevates cAMP and switches on protein kinase A, leading to CREB-dependent changes in gene transcription. Some systems also show coupling to phospholipase C, and both receptors recruit beta-arrestin and internalise.

The two receptors are expressed in different places — VPAC1 predominates in lung, liver and lymphocytes, while VPAC2 is prominent in smooth muscle, the suprachiasmatic nucleus and pancreatic islets, among other sites — so one ligand gives quite different results from tissue to tissue. For that reason much VIP research relies on subtype-selective analogues rather than the native peptide, in order to assign an effect to one receptor rather than both.

Most of the physiology described for VIP follows from three downstream effects of higher cAMP. In smooth muscle, PKA activity lowers contractile tone, which underlies the vasodilation and bronchial relaxation seen in the early experiments. In immune cells, raised cAMP is generally linked in published work to lower production of pro-inflammatory cytokines and changes in T-cell phenotype. In suprachiasmatic nucleus neurons, VPAC2 signalling is reported to be essential for synchronising the circadian clock — VPAC2-knockout mice show severely disturbed circadian rhythms.

One practical property dominates everything else: native VIP does not last long. Dipeptidyl peptidase-4 and other peptidases degrade it, and its reported half-life in plasma is measured in minutes. An entire applied literature is devoted to stabilised analogues and delivery systems, and any experiment exposing the native peptide to active proteases has to allow for rapid loss.

Research applications

Immunomodulation and inflammation

VIP features widely in studies of macrophage and dendritic cell phenotype, induction of regulatory T cells and cytokine patterns, as well as in rodent models of autoimmune and inflammatory conditions. This is the thread that puts it next to KPV and LL-37 in inflammation-focused catalogues, although their mechanisms have nothing in common: VIP is a class B GPCR agonist, KPV an intracellular modulator of NF-kappa B, and LL-37 a membrane-active host-defence peptide.

Gastrointestinal physiology

Because VIP is a key transmitter of inhibitory motor neurons in the enteric nervous system, it is studied in relation to smooth muscle relaxation, sphincter function, secretion and barrier integrity. Researchers exploring epithelial barrier questions frequently use it together with larazotide acetate, which targets tight junctions directly instead of acting through a receptor.

Respiratory and pulmonary research

Bronchodilation, regulation of pulmonary vascular tone and models of pulmonary hypertension make up a separate strand of work, parts of which have progressed to clinical study of VIP analogues rather than the native molecule.

Chronobiology and neuroscience

The VIP-expressing neurons of the suprachiasmatic nucleus are a central theme in circadian biology, with VPAC2 signalling implicated in coupling pacemaker cells to one another. Independently, VIP is investigated in neuroprotection and neurodevelopment.

Receptor pharmacology

Native VIP serves as the standard reference agonist in VPAC1 and VPAC2 binding assays and cAMP accumulation assays — probably its most common use at the bench, and one that relies completely on the material being properly amidated and of confirmed purity.

Everything described above is preclinical or in-vitro research. Native VIP is not authorised as a medicine, and clinical studies in this area have involved analogues and formulations, not research-grade peptide.

Available formats and vial sizes

We supply VIP as a lyophilized powder in sealed vials of 5 mg (€115) and 10 mg (€200). With a molecular weight of 3326.80 g/mol, one 5 mg vial holds roughly 1.5 micromoles. Receptor assays generally run at nanomolar concentrations, so that amount goes a long way in pharmacology, whereas formulation and in-vivo studies use it up much more quickly. Related compounds are listed under anti-inflammatory peptides, and our VIP buying guide explains what to check before ordering.

Reconstitution and storage at the bench

Worked example: dissolving a 5 mg vial in 1 mL of diluent yields 5 mg/mL — that is, 5,000 mcg/mL or about 1.50 mM. Diluting this stock 1:1,000 gives 1.5 micromolar, and a further 1:100 step gives 15 nanomolar, the kind of dilution series a VPAC binding assay really needs. Calculating molarity explicitly, instead of thinking in micrograms, prevents the most frequent arithmetic mistake in receptor pharmacology.

The central part of the VIP sequence is somewhat hydrophobic, so handle it gently: run the diluent slowly down the inside of the vial, swirl instead of shaking, and let the cake dissolve without vortexing. At low concentrations VIP adsorbs noticeably to plastic, so low-binding tubes — and, where suitable, a carrier protein in the assay buffer — are routine. Methionine at position 17 is prone to oxidation, a practical reason to keep stock solutions away from air and light. Store lyophilized vials at −20 °C or below, protected from moisture; aliquot reconstituted material and keep it refrigerated or frozen to avoid repeated warming. The peptide storage guide gives the complete protocol.

Purity and reading the certificate of analysis

Every lot is purified by reversed-phase HPLC to 99% or higher, confirmed by mass spectrometry and shipped with a certificate matched to the lot. Two checks apply specifically to VIP. The first is the amide: the measured mass should match 3326.80 g/mol for the amidated form, and a result roughly 1 Da higher points to the free acid — the most important identity check for this peptide, read straight off the mass spectrum. The second is oxidation: because VIP contains methionine, degradation during synthesis or storage can show up as a +16 Da satellite in the mass spectrum and as an early-eluting shoulder in the chromatogram. Otherwise the usual rules apply — look at the chromatogram itself rather than only the headline figure, and compare net peptide content with the gross weight in the vial. Our COA reading guide explains both points in depth.

Regulatory position

Although VIP occurs naturally in humans, the synthetic material we supply is not an authorised medicine, not a food supplement and not a routinely available compounded product. Published physiological data refer to the endogenous peptide and to investigational analogues and do not constitute claims for research-grade material, which is sold strictly for laboratory research and not for human use.

Related compounds and further reading

Other members of the secretin-glucagon superfamily in this catalogue include the GHRH analogues sermorelin and tesamorelin, which have the same structural fold and class B receptor mechanism but act on a completely different receptor. For gut-focused background, see the gut health research overview; institutional listings group associated products on the VIP family page.