A NEW VASOACTIVE-INTESTINAL-PEPTIDE ANTAGONIST DISCRIMINATES VIP RECEPTORS ON GUINEA-PIG TRACHEA AND HUMAN NEUROBLASTOMA-CELLS

VIP is a widely distributed neuropeptide of 28 amino acids, whose cent ral part is proposed to be an amphiphilic alpha-helix. In order to gai n an understanding of the effect of this alpha helix on receptor bindi ng and stimulation, a human VIP analog has been designed in which the residues 12 to 19 were replaced by a spacer of the same length, (gamma -aminobutyryl)(2). This peptide altered neither the basal guinea pig t racheal smooth muscle tonus nor the VIP-induced relaxation. Conversely , the VIP analog was found to displace VIP from its binding sites on L A-N-2 human neuroblastoma cells (VIP IC50:5.4 nM; VIP analog IC50:52.2 nM) and to inhibit the VIP-induced cyclic AMP production of 58 +/- 15 % at 1 mu M and 95 +/- 2% at 10 mu M. It seems that the alpha helix st ructure might only play the role of a spacer holding the important res idues, at the N- and C-ends, respectively, at an appropriate distance. In the VIP analog structure, the (gamma-aminobutyryl)(2) chain introd uced in place of the alpha helix plays the role of adequate spacer to bind the LA-N-2 receptors but probably does not induce the active conf ormation for receptor stimulation. The lack of VIP analog effects on t he tracheal receptors related to relaxation argues for a possible hete rogeneity of VIP receptors on a pharmacological basis.