[d‐Phe⁴]Peptide histidine‐isoleucinamide ([d‐Phe⁴]PHI), a highly selective vasoactive‐intestinal‐peptide (VIP) agonist, discriminates VIP‐preferring from secretin‐preferring receptors in rat pancreatic membranes

Abstract

The capacity of vasoactive intestinal peptide (VIP), peptide histidine‐isoleucinamide (PHI), secretin, and a series of analogs to discriminate between VIP‐preferring and secretin‐preferring receptors that coexist in rat pancreatic plasma membranes was evaluated by their ability to inhibit [125I]iodo‐VIP and [125I]iodo‐secretin binding and to activate adenylate cyclase. VIP, the VIP analogs [d‐His1]VIP, [d‐Ser2]VIP, [d‐Asp3]VIP and [d‐Ala4]VIP, PHI, [d‐Phe4]PHI, and secretin inhibited the binding of both ligands in a concentration range of 10−11 M to 10−5 M and with a selectivity factor varying from 18000 to 0.1. The only exception was [d‐Phe4]PHI that inhibited 125I‐VIP binding only, with an IC50 of 7 nM, and with no inhibition of 125I‐secretin binding at 10 μM. The peptides tested stimulated adenylate cyclase in the same membranes and the slope of the dose‐effect curves indicated that all peptides, except [d‐Phe4]PHI, interacted with at least two classes of receptors: VIP‐preferring and secretin‐preferring receptors. By contrast, the dose‐effect curve of [d‐Phe4]PHI activation of adenylate cyclase was monophasic and competitively modified by [d‐Phe2]VIP (a VIP antagonist) but not by secretin(7–27) (a secretin antagonist), indicating an interaction with VIP‐preferring receptors only. Thus, [d‐Phe4]PHI appears to be a highly selective tool to characterize these receptors.

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

“…During the last four decades, many ligands have been developed, both agonists and antagonists for VIP receptors. Most of them were created by modifying endogenous peptides and displayed different affinities and selectivities, with the first descriptions unable to differentiate between the two receptors [56][57][58]. Selective agonists for VPAC1 receptor have been generated, such as [K 15 , R 16 , L 27 ]VIP(1-7)/GRF (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) [59], [Ala 11,22,28 ]VIP [60], [L 22 ]VIP [61], [R 16 ]PACAP(1-23) [62], and LBT-3393 [63].…”