Key findings
- The original isolation from hog small intestine established a polypeptide of 28 amino acid residues that is chemically distinct from the kinins, substance P, glucagon and secretin. [1]
- The cloned human VIP-2 receptor expressed in COS-7 cells bound iodinated peptide with a half maximal inhibitory concentration of 0.93 nM, displaced by unlabelled PACAP-38 at 6.2 nM, and the two peptides were equipotent at raising cAMP. [2]
- A cryo-electron microscopy structure of the human VIP1 receptor coupled to Gs shows the ligand N-terminus inserted into the binding pocket of the transmembrane bundle, with G protein coupling in a receptor-specific manner. [3]
- Limited proteolysis showed that a receptor extracted with digitonin keeps a protease sensitivity pattern close to the membrane-bound protein, while extraction with Triton X-100 gives increased protease sensitivity and different cleavage products. [4]
Identity and structure
- Origin
- Isolated from the small intestine of the hog and shown to be chemically distinct from the kinins, substance P, glucagon and secretin [1]
- Receptors
- Two class B G protein-coupled receptor subtypes, VPAC1 and VPAC2, the second of which encodes a 438 residue protein from a 1317 base pair cDNA [5][2]
- Metabolic stability
- The native 28-residue peptide is reported as rapidly degraded, which is why the cited analogue work sought stabilized substitutions [5]
- Form as supplied
- Sterile lyophilized powder
Mechanism as studied
Receptor engagement follows the two-domain pattern described for class B receptors. Photoaffinity labelling with NMR and molecular modelling place most of the 1-28 alpha-helical peptide against the N-terminal ectodomain of VPAC1, which is itself folded as a Sushi domain, while a specific antagonist contacts a different region of the same ectodomain. [6]
The transmembrane half of that interaction is what the structural work resolves. In the activated receptor complex the ligand N-terminus inserts into the pocket of the transmembrane bundle and the receptor then couples to Gs, although the ligand in that structure is PACAP27 rather than this peptide. [3]
Subtype discrimination is a matter of sequence positions rather than of a separate binding mode. Alanine substitution across nine simplified analogues produced two with more than 2000-fold and more than 600-fold selectivity for VPAC1, while none of the nine achieved VPAC2 selectivity. [5]
Research findings
Analytical
- System
- Extract of hog small intestine, purified and characterized chemically
- Measured
- Amino acid residue count of the purified polypeptide and its chemical distinction from previously known peptides
- Reported
- The purified polypeptide has 28 amino acid residues and is chemically distinct from the kinins, substance P, glucagon and secretin. [1]
In vitro
- System
- Human placenta cDNA library and COS-7 cells transfected with the cloned VIP-2 receptor, plus Northern blots of human tissue
- Measured
- Sequence and predicted protein length of the clone, iodinated peptide binding and its displacement by unlabelled PACAP-38, cAMP accumulation, and receptor mRNA sizes and tissue distribution
- Reported
- The 1317 base pair insert encodes a 438 residue seven transmembrane receptor. Iodinated peptide bound with a half maximal inhibitory concentration of 0.93 nM and PACAP-38 displaced it at 6.2 nM, and the two were equipotent at raising cAMP. Two receptor mRNAs of 4.6 kb and 2.3 kb were seen, predominantly in skeletal muscle and to a lesser extent in brain, heart, pancreas and placenta. [2]
Structural
- System
- Human VIP1 receptor in complex with PACAP27 and a Gs heterotrimer, stabilized by a NanoBiT tethering strategy, so the resolved ligand is the related PACAP27 peptide rather than this peptide
- Measured
- The cryo-electron microscopy structure of the activated receptor G protein complex and the comparison of its ligand pose with other class B receptor structures
- Reported
- The ligand engages the receptor with its N-terminus inserted into the binding pocket at the transmembrane bundle, and the receptor then couples to the G protein in a receptor-specific way. The authors also present the tethering strategy as a route to structures of unstable complexes. [3]
In vitro
- System
- Rat lung receptor preparations compared in the membrane-bound state and after solubilization in digitonin or in Triton X-100, covalently labelled with iodinated peptide
- Measured
- Retention of iodinated peptide binding after extraction, and protease sensitivity and cleavage product patterns under trypsin, chymotrypsin or carboxypeptidase Y
- Reported
- Digitonin extracted receptor retained binding and resembled the membrane-bound protein in protease sensitivity and cleavage products. Triton X-100 extracted receptor showed little or no detectable binding, increased protease sensitivity and distinctly different cleavage patterns, which the authors read as a detergent dependent change in folded state. [4]
In vitro
- System
- Nine simplified alanine-substituted analogues of the peptide tested on T47D and transfected cells expressing human VPAC1 and on Sup T1 and transfected cells expressing human VPAC2, so the selectivity results describe the analogues rather than the native sequence
- Measured
- Direct binding affinity at each receptor subtype, adenylate cyclase stimulation and metabolic stability of an iodinated analogue against iodinated native peptide
- Reported
- Two analogues showed more than 2000-fold and more than 600-fold selectivity for VPAC1, none of the nine was VPAC2 selective, and two others kept high affinity and potency at both subtypes. One iodinated analogue was much more metabolically stable than the iodinated native peptide. [5]
Review
- System
- Review of structure-function work on the VPAC1 receptor, including the authors' own photoaffinity labelling, NMR, molecular modelling and molecular dynamics results
- Measured
- Narrative assembly of the binding determinants, the ectodomain fold and the contact regions of agonist and antagonist
- Reported
- Most of the 1-28 alpha-helical peptide binds tightly to the N-terminal ectodomain of the receptor, which is structured as a Sushi domain, while the N-terminal part of the antagonist PG97-269 contacts that ectodomain in a different region. [6]
Review
- System
- Review of activation and signal transduction in the VPAC1 receptor as a class B G protein-coupled receptor
- Measured
- Narrative assembly of the residues implicated in the two-step binding process and in stabilizing inactive and active receptor conformations
- Reported
- The review states that the precise structural basis for ligand binding, receptor activation and signal transduction remains incompletely understood, in part because no X-ray crystal structure of the whole receptor was available. [7]
Handling for in-vitro work
- Detergent choice in cited work
- Digitonin extraction preserved receptor binding and folded state while Triton X-100 extraction did not [4]
- Degradation
- The native sequence is reported as rapidly degraded, so freshly prepared solutions were used in the cited binding work [5]
- Storage
- Lyophilized at -20 °C, dark and dry; reconstituted aliquots kept cold and used promptly
Open questions
- No structure of a receptor bound to this peptide itself appears in the cited set; the resolved activated complex carries the related PACAP27 ligand.
- The cited review notes the absence of an X-ray crystal structure of the whole VPAC1 receptor, which leaves the two-domain binding model partly inferred.
- None of the nine simplified analogues achieved VPAC2 selectivity, so the sequence determinants of that subtype remain unresolved in the cited work.
- The tissue distribution reported by Northern blot is at the transcript level and the cited work does not measure receptor protein across the same tissues.
A clinical literature on this peptide and its receptor subtypes exists and concerns finished formulations and imaging agents; it is out of scope for a research material profile and none of it is summarized here.
Lot records
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Read a certificate of analysis ↗References
- Said SI, Mutt V Polypeptide with broad biological activity: isolation from small intestine. Science (New York, N.Y.). 1970.
- Adamou JE, Aiyar N, Van Horn S, et al. Cloning and functional characterization of the human vasoactive intestinal peptide (VIP)-2 receptor. Biochemical and biophysical research communications. 1995.
- Duan J, Shen DD, Zhou XE, et al. Cryo-EM structure of an activated VIP1 receptor-G protein complex revealed by a NanoBiT tethering strategy. Nature communications. 2020.
- Provow SA, Veliçelebi G Limited proteolysis of the vasoactive intestinal peptide receptor: comparison of its folded structure in the membrane-bound and detergent-solubilized states. Regulatory peptides. 1990.
- Igarashi H, Ito T, Mantey SA, et al. Development of simplified vasoactive intestinal peptide analogs with receptor selectivity and stability for human vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide receptors. The Journal of pharmacology and experimental therapeutics. 2005.
- Couvineau A, Ceraudo E, Tan YV, et al. VPAC1 receptor binding site: contribution of photoaffinity labeling approach. Neuropeptides. 2010.
- Langer I Conformational switches in the VPAC(1) receptor. British journal of pharmacology. 2012.
Publication records fetched from PubMed on 2026-09-20. Profile text reviewed 2026-09-20.