Addition of the (28-38) peptide sequence of PACAP to the VIP sequence modifies peptide selectivity and efficacy.

Chimeric peptides were synthesized by adding the C-terminal extension 28-38 of the pituitary adenylate cyclase activating polypeptide (PACAP) to the sequences (1-27), (2-27), (3-27) and (6-27) of VIP. The capacity of these peptides to occupy the selective PACAP- and the non-selective PACAP-VIP receptors and to stimulate adenylate cyclase activity was studied in chinese hamster ovary (CHO) cells expressing the recombinant receptors. The results were compared to those obtained with VIP and the corresponding VIP fragments. The presence of the (28-38) PACAP extension increased at least 100-fold the VIP- or VIP fragment affinities for the selective PACAP receptor but not for the non-selective PACAP-VIP receptors. Furthermore, on both receptors, the extension increased peptide intrinsic activity: VIP(3-28) was a partial agonist while VIP(3-27)/PACAP(28-38) was as potent as VIP and was apparently a full agonist; VIP(6-28) had no intrinsic activity, but VIP(6-27)/PACAP(28-38) was a partial agonist. These results suggest: (1) the presence of a specific domain for the (28-38) PACAP sequence on the selective PACAP receptor; and (2) a stabilizing effect of the (28-38) PACAP sequence on the structure of N-terminally truncated VIP.