VIP (Vasoactive Intestinal Peptide): VPAC1 and VPAC2 Receptor Research

VIP was isolated from porcine small intestine in 1970 and has since been located throughout central and peripheral nervous tissue. The mature 28-residue peptide is excised from a 170-residue precursor, prepro-VIP, encoded by the VIP gene at human chromosome 6q25.2, and carries an amide group in place of the free C-terminal carboxylate.

PubChem records the amidated peptide under CID 53314964 with the formula C147H237N43O43S and a molecular weight of 3326.8 g/mol, against CAS registry number 37221-79-7. The single-letter sequence HSDAVFTDNYTRLRKQMAVKKYLNSILN contains one methionine at position 17, two arginines, three lysines and no cysteine, so the molecule has no disulfide bond and no intrinsic constraint on its backbone beyond secondary structure.

The same precursor yields a second bioactive product. UniProt P01282 annotates peptide histidine methionine (PHM-27) at residues 81 to 107 and the mature peptide at residues 125 to 152, both amidated. Because the two are cleaved from one polypeptide, tissue that expresses the gene generally releases both, which is worth noting when interpreting immunoassay data from tissue extracts.

Computed descriptors match the behaviour of a highly polar polypeptide rather than a small molecule. PubChem lists an XLogP of -15.9, a topological polar surface area of 1470 Ų, 51 hydrogen bond donors, 51 hydrogen bond acceptors and 115 rotatable bonds. Nothing in that profile suggests membrane partitioning, and the receptor pharmacology below is correspondingly extracellular.

VIP acts at two class B1 G protein-coupled receptors, VPAC1 (gene VIPR1) and VPAC2 (gene VIPR2), and far more weakly at the PACAP-preferring receptor PAC1. The IUPHAR review of this receptor family lists radioligand binding affinities at cloned human receptors of pKi 8.5 to 9.8 for VPAC1 and 7.8 to 8.8 for VPAC2.

At PAC1 the same compilation records pKi 6.0 to 6.3, roughly two to three orders of magnitude weaker than at VPAC1. That gap is the basis of the standard pharmacological division of the family: PAC1 is the PACAP-selective receptor, while VPAC1 and VPAC2 accept both endogenous peptides with comparable potency. Any experiment that attributes an effect to one subtype needs subtype-selective tools rather than concentration alone.

Which G proteins each receptor recruits was examined directly in a 2026 BRET study in Jurkat T cells. VPAC1 interacted with both Gαs and Gαq subunits, whereas VPAC2 preferentially engaged Gαs. Both receptors raised cyclic AMP when stimulated, but calcium responses appeared only through VPAC1, which supplies a functional readout that distinguishes the two subtypes in the same cell background.

Selective peptide tools recur across the electrophysiology and immunology literature. PG97-269 is used as a VPAC1 antagonist and PG99-465 as a VPAC2 antagonist, while VIPhyb is the long-standing hybrid antagonist scaffold from which newer, higher-affinity variants have been derived. Reports that use these reagents in parallel are the ones that can assign an observation to a specific receptor subtype.

VIP bound to VPAC1 was resolved by cryo-electron microscopy in 2022 at a global resolution of 2.7 Å in complex with heterotrimeric Gs, deposited as Protein Data Bank entry 8E3Z. Companion structures of PACAP27 on VPAC1 and on PAC1 reached 2.3 Å, allowing two related peptides to be compared on the same receptor scaffold.

The comparison is asymmetric in an informative way. The structural analysis counted seven hydrogen bonds between the peptide and VPAC1, against ten for PACAP27 at both receptors, and molecular dynamics simulations showed markedly more extensive movement of the peptide against extracellular loop 3. Fewer stable contacts and a more mobile interface distinguish this ligand from its close relative on the identical receptor.

Solution biophysics had already established why the free peptide is mobile. NMR work published in Biochimica et Biophysica Acta reported that glycine-extended peptide is unstructured in aqueous solution, showing limited chemical shift dispersion, and folds into a disordered N-terminal region followed by a long α-helix only on contact with membrane mimetics. In micelles that helix is curved, with the side chains of Phe6, Tyr10, Leu13 and Met17 forming a hydrophobic patch on the concave face.

Simulations in the 2022 work also modelled the peptide into PAC1 and predicted more transient contacts in that receptor core than in VPAC1, which the authors advance as a structural account of the selectivity gap the binding tables record. Together the structural and solution data explain why substitutions in the C-terminal half of the sequence have been the productive route to higher-affinity antagonists.

VIP signaling in lymphocytes is the most heavily worked area of the current literature. Reports describe the peptide raising cyclic AMP through VPAC1 and VPAC2 on T cells, reducing phosphorylation of inflammatory kinase-associated proteins, and acting as an endogenous brake on T cell activation that purpose-built antagonist peptides are designed to lift.

The 2026 Jurkat study built stable lines overexpressing each receptor and read out cyclic AMP, calcium, kinase phosphorylation, immune mediator expression, survival and proliferation. Receptor overexpression alone shifted baseline transcriptional patterns, and peptide exposure lowered phosphorylation of inflammatory kinase-associated proteins in both lines. Proliferation was unchanged, though the VPAC2-overexpressing line showed reduced metabolic activity at 72 hours, and the subtype differences that were clear at early signaling steps converged once the T cell receptor was engaged.

Antagonist chemistry has moved quickly. A 2026 Journal of Biological Chemistry report screened a combinatorial library of C-terminal sequence variants of the VIPhyb scaffold, synthesised 15 candidates, and ranked them by predicted receptor binding, potency in T cell activation assays and activity in murine acute myeloid leukemia models. ANT308 and ANT195 emerged as leads; ANT308 decreased CREB phosphorylation, a downstream readout of receptor engagement, and raised granzyme B and perforin expression in human CD8-positive T cells.

The same axis has been engineered into cell products. A 2026 Science Translational Medicine study reported that the peptide suppresses chimeric antigen receptor T cell function, then built CAR T cells that secrete a short receptor-antagonist peptide. Those cells held a memory phenotype and were metabolically quiescent after manufacture, mounted a strong metabolic response on antigen stimulation, recruited host T cells, and showed greater tumour infiltration in syngeneic and xenogeneic mouse models of haematological and solid tumours.

VIP is expressed by enteric neurons along the length of the gut wall, and 2024 to 2026 work maps a neuroepithelial circuit in which the peptide acts on VIPR1-positive intestinal stem cells. Separate rodent work places peptide-expressing neurons of the suprachiasmatic nucleus at the centre of light-driven changes in memory accessibility.

The Nature Immunology report from 2025 identified peptide-positive enteric neurons acting on VIPR1-positive epithelial stem cells to restrain both proliferation and secretory lineage differentiation. Disrupting that pathway expanded tuft cells, raised interleukin-25 production, activated group 2 innate lymphoid cells and induced a type 2 immune programme resembling worm expulsion. The phenotype was independent of the microbiota but modulated by the IL-25R-ILC2-IL-13 axis and by dietary solids.

Organoid work from 2024 had approached epithelial turnover from the injury side. Jejunal organoids from C57BL/6, Lgr5-EGFP-IRES-CreERT2 and lineage-tracing reporter mice were exposed to the peptide and irradiated at 6 Gy in vitro, with a parallel arm in mice receiving 12 Gy abdominal irradiation. The peptide pushed epithelial differentiation toward secretory phenotypes primarily through p38 MAPK signaling, modulated Lgr5-EGFP-positive progenitor activity, and promoted regeneration after acute irradiation injury.

In the brain, a 2025 Neuroscience Bulletin study reported that acute bright light selectively impaired trace fear memory by activating suprachiasmatic peptide neurons, evidenced by increased c-Fos expression and calcium recording. Optogenetic and chemogenetic manipulation reproduced and reversed the effect, and the projection from the suprachiasmatic nucleus to the paraventricular nucleus of the thalamus proved essential, extending the role of these neurons beyond circadian timing.

Peripheral neuron recordings supply concentration figures. Whole-cell patch-clamp work on myelinated Ah-type trigeminal ganglion neurons from adult female rats reported that 100 nM peptide raised repetitive firing frequency, narrowed the action potential, increased downstroke velocity and deepened after-hyperpolarisation. Iberiotoxin reversed those changes except the after-hyperpolarisation, which apamin abolished, and PG97-269 blocked the response completely while PG99-465 did not, pointing to VPAC1.

VIP research published across 2025 and 2026 spans ocular pressure regulation, viral entry biology, lymphocyte signaling and peripheral neuron excitability. Working concentrations differ by orders of magnitude between those systems, from 100 nM in single-neuron electrophysiology upward, so a figure quoted without its model system carries very little information.

Ocular work published in Annals of Medicine in 2025 used two paired systems: rats in which three episcleral veins were cauterised, and human trabecular meshwork cells under pressure stimulation. Both models raised the tight junction proteins ZO-1 and Claudin-1. Peptide exposure and Rab13 overexpression each lowered those proteins in pressure-stimulated cells, Rab13 knockdown reversed the peptide effect, and in the rat model the peptide reduced ZO-1, Claudin-1 and trabecular tissue density alongside lower intraocular pressure.

A 2025 International Journal of Molecular Sciences study examined the peptide against SARS-CoV-2 entry machinery in CaCo-2 epithelial cells stimulated with spike protein. The peptide downregulated ACE2 and TMPRSS2 at both the messenger RNA and surface protein level, and separately drove shedding of the surface-expressed proteins by upregulating the sheddase ADAM10. Infection rate by a SARS-CoV-2 pseudovirus fell as a result, and the authors flag the ADAM10 link as the generalisable mechanism.

Read together, the recent record is notable for how consistently receptor subtype identity, rather than peptide concentration, decides the reported outcome. The 2026 lymphocyte work separates VPAC1 from VPAC2 by calcium coupling, the trigeminal recordings separate them by antagonist reversal, and the antagonist and CAR T reports make receptor engagement itself the variable under study. That convergence is the most useful organising fact for anyone reading the field as of August 2026.

VIP is supplied as a lyophilized powder, and the computed profile matches that format precisely. An XLogP of -15.9, a topological polar surface area of 1470 Ų and 51 hydrogen bond donors describe an extremely hydrophilic solid with no lipophilic character, so published methods prepare working solutions in aqueous buffer, saline or culture medium rather than organic solvent.

Peptide solutions of this class adsorb to glass and untreated plastic at low concentrations, which is why cell-assay protocols commonly include carrier protein in the diluent and why the peptide is normally aliquoted rather than repeatedly thawed. The molecule has no cysteine and therefore no disulfide to scramble, but the single methionine at position 17 is an oxidation-sensitive residue and sits inside the hydrophobic patch identified in the NMR work, so oxidative conditions are the chemistry most likely to matter.

Circulating stability is the practical constraint the literature works around. Reviews of this peptide family describe rapid clearance and enzymatic breakdown as the reason so much of the delivery work uses liposomal encapsulation, nanoparticle carriers or sequence-modified analogues; the 2026 antagonist screen explicitly listed plasma stability alongside receptor affinity as a design target for its C-terminal variants.

Working concentrations in the published record vary widely by model type, so a figure quoted without its system is not interpretable. Trigeminal neuron electrophysiology used 100 nM, and the receptor binding tables put affinities in the low nanomolar range, consistent with pKi 8.5 to 9.8 at VPAC1; cell-culture and organoid protocols generally sit well above those figures because the peptide is consumed and degraded over a multi-day incubation. Identity is confirmed by electrospray mass spectrometry against a monoisotopic mass of 3324.7401 Da, which for a 3.3 kDa peptide appears as a series of multiply charged ions, with purity determined by reversed-phase HPLC and reported on the lot certificate of analysis.

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