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 central part is proposed to be an amphiphilic alpha-helix. In order to gain an understanding of the effect of this alpha helix on receptor binding 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 tracheal smooth muscle tonus nor the VIP-induced relaxation. Conversely, the VIP analog was found to displace VIP from its binding sites on LA-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 microM and 95 +/- 2% at 10 microM. It seems that the alpha helix structure might only play the role of a spacer holding the important residues, at the N- and C-ends, respectively, at an appropriate distance. In the VIP analog structure, the (gamma-aminobutyryl)2 chain introduced 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 conformation for receptor stimulation. The lack of VIP analog effects on the tracheal receptors related to relaxation argues for a possible heterogeneity of VIP receptors on a pharmacological basis.
Leroux
F
F
Institut de Chimie Pharmaceutique de Lille, Faculté des Sciences Pharmaceutiques et Biologiques, France.
Goossens
J F
JF
Pommery
N
N
Hénichart
J P
JP
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009126:Muscle Relaxation / Q000187:drug effects; D009447:Neuroblastoma / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D018005:Receptors, Vasoactive Intestinal Peptide / Q000187:drug effects / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000235:genetics
D010446:Peptide Fragments; D018005:Receptors, Vasoactive Intestinal Peptide; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP