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Related Experiment Videos

Vasoactive intestinal peptide modification at position 22 allows discrimination between receptor subtypes

P Gourlet1, M C Vandermeers-Piret, J Rathé

  • 1Department of Biochemistry and Nutrition, School of Medicine, Université Libre de Bruxelles, Brussels, Belgium.

European Journal of Pharmacology
|July 3, 1998
PubMed
Summary

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Researchers investigated specific amino acid changes in vasoactive intestinal peptide (VIP) to understand its receptor selectivity. An aromatic residue at position 22 is crucial for high affinity to VIP2/PACAP receptors, but not VIP1/PACAP receptors.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) receptors are crucial in various physiological processes.
  • Secretin and growth hormone-releasing factor (GRF) exhibit weak affinity for VIP/PACAP receptors, yet show selectivity between VIP1/PACAP and VIP2/PACAP subtypes.
  • Previous work successfully developed modified secretin and GRF analogs as high-affinity, selective ligands for VIP1/PACAP receptors.

Purpose of the Study:

  • To elucidate the structural basis for VIP receptor subtype selectivity.
  • To test the hypothesis that glutamine (Gln) at position 24 and leucine (Leu) at position 22 in VIP are responsible for VIP1/PACAP receptor selectivity.

Main Methods:

  • Site-directed mutagenesis was used to create modified VIP analogs with specific amino acid substitutions.

Related Experiment Videos

  • Radioligand binding assays were performed to determine the binding affinities of wild-type VIP and its analogs to VIP1/PACAP and VIP2/PACAP receptors.

    • Main Results:

    • The [Gln24]VIP analog showed no significant difference in affinity compared to wild-type VIP for either receptor subtype.
    • [Leu22]VIP exhibited a 100-fold lower affinity for VIP2/PACAP receptors compared to VIP1/PACAP receptors.
    • Substitution of tyrosine (Tyr) at position 22 with phenylalanine (Phe) did not alter receptor recognition, whereas substitution with alanine (Ala) reduced affinity for the VIP2/PACAP receptor.

    Conclusions:

    • An aromatic residue at position 22 of VIP is essential for high-affinity binding to the VIP2/PACAP receptor.
    • This aromaticity at position 22 is not required for high-affinity binding to the VIP1/PACAP receptor.
    • These findings provide critical insights into the molecular determinants of VIP receptor subtype selectivity.