Analogues of VIP, helodermin, and PACAP discriminate between rat and human VIP1 and VIP2 receptors

Area of Science:

• Pharmacology
• Receptor Biology
• Neuroendocrinology

Background:

• Vasoactive intestinal polypeptide (VIP) mediates its effects via VIP1 and VIP2 receptors, which are G protein-coupled receptors.
• These receptors exhibit distinct distributions, driving interest in developing selective agonists and antagonists.
• Understanding ligand-receptor interactions is key for therapeutic development.

Purpose of the Study:

• To compare the binding affinities of various VIP, PACAP, GRF, secretin, and helodermin analogues on recombinant rat and human VIP1 and VIP2 receptors.
• To identify specific structural domains within these ligands that confer selectivity for VIP1 versus VIP2 receptors.
• To explore species-specific differences in ligand binding to VIP receptors.

Main Methods:

• Recombinant expression of rat and human VIP1 and VIP2 receptors.
• Binding assays using a panel of VIP, PACAP, GRF, secretin, and helodermin analogues.
• Analysis of ligand affinity and selectivity across different receptor subtypes and species.

Main Results:

• Secretin and GRF showed higher affinity for VIP1 receptors (both rat and human).
• Amino- and carboxy-terminal shortened VIP and PACAP analogues also favored VIP1 receptors.
• PHI, PHV, helodermin, and helospectin were selective for human VIP2 receptors, suggesting a role for the carboxy-terminal helical structure.
• Species differences were observed, with PHI, PHV, helodermin, and helospectin showing higher affinity for rat VIP1 receptors.
• [D-Ala4]VIP and [D-Phe4]VIP exhibited high affinity for VIP1 and low affinity for VIP2 receptors on both species.

Conclusions:

• Three key ligand domains were identified for VIP1/VIP2 receptor discrimination: residue at position 4, residues 8 and 9, and the carboxy-terminal end.
• These findings provide critical insights into the structural basis of VIP receptor subtype selectivity.
• The study lays the groundwork for designing novel peptide analogues with enhanced specificity for therapeutic applications targeting the VIPergic system.