Interaction of Synthetic 10-Tyrosyl Analogues of Secretin with Hormone Receptors on Pancreatic Acinar Cells

Abstract

Four synthetic analogues of secretin [(10-tyrosine), (4-alanine, 10-tyrosine), (3-glutamine, 10-tyrosine), and (3-glutamic acid, 10-tyrosine)] were tested for their ability to interact with hormone receptors on dispersed acinar cells prepared from guinea pig pancreas. [10-tyrosine]Secretin inhibited binding of 125 I vasoactive intestinal peptide (VIP) to the same extent as did native secretin. Thus, substituting tyrosine for leucine in position 10 of porcine secretin makes the peptide structurally more like porcine VIP but does not make the peptide more VIP-like in terms of its ability to interact with the high affinity VIP receptor. Although VIP has alanine in position 4, substituting alanine for glycine in position 4 of [10-tyrosine]secretin made the peptide functionally less VIP-like in that it reduced the ability of the peptide to .inhibit binding of 125 I-VIP. Each of the 4 analogues interacted with the high affinity secretin receptor to increase cellular accumulation of cyclic AMP. The 10-tyrosine analogue was approximately one-tenth as potent as secretin. In [10-tyrosine]secretin adding one methyl group to the side chain of the amino acid in position 4 (replacing glycine by alanine), or interposing a methyl group in the acidic side chain of the residue in position 3 (replacing aspartic acid by glutamic acid), reduced the apparent affinity of the peptide for the high affinity secretin receptor by 15- or 40-fold, respectively. These results illustrate how changes in the amino-terminal region of secretin, which in terms of peptide structure might appear to be relatively trivial, can produce substantial changes in the apparent affinity of secretin for its receptors.