C-terminal peptides of calcitonin gene-related peptide act as agonists at the cholecystokinin receptor

Abstract

We have previously described that [Tyr0]CGRP(28-37) acts as a receptor antagonist of rat CGRP in guinea pig pancreatic acini. We therefore examined other C-terminal peptides of CGRP for such activity. CGRP-acetyl(28-37) acetate did act as a rat CGRP antagonist. However, C-terminal CGRP peptides of 4 to 8 amino acid residues did not antagonize the actions of rat CGRP but stimulated amylase secretion. In pancreatic acini, a maximally effective concentration of rat CGRP (100 nM) caused a 2.1-fold increase in amylase secretion. When the C-terminal peptides of CGRP were tested in at 100 microM, CGRP(34-37) caused a 1.8-fold increase in amylase secretion, CGRP(33-37) a 2.8-fold increase. CGRP(32-37) a 9.2-fold increase, CGRP(31-37) a 4.1-fold increase, and CGRP(30-37) a 5.1-fold increase. Further studies with the most effective peptide, CGRP(32-37), demonstrated that it did not cause release of lactate dehydrogenase, and thus did not cause amylase release by cell damage. Unlike rat CGRP, CGRP(32-37) did not increase cellular cyclic AMP, but did stimulate outflux of 45Ca. CGRP(32-37)-stimulated amylase release was not inhibited by the substance P receptor antagonist, spantide, by the bombesin receptor antagonist, [D-Phe6]bombesin(6-13) propylamide, or by the muscarinic receptor antagonist, atropine, but was inhibited by the CCK receptor antagonist L364,718. C-terminal peptides of CGRP inhibited binding of 125I-BH-CCK-8, with the relative potencies of the peptides being the same as their relative potencies for stimulating amylase secretion.(ABSTRACT TRUNCATED AT 250 WORDS)