Mechanism of action of calcitonin gene-related peptide in stimulating pancreatic enzyme secretion.

In guinea pig pancreatic acini rat calcitonin gene-related peptide (CGRP) caused an eightfold increase in amylase release with various phosphodiesterase inhibitors present. Rat CGRP and rat [Tyro]CGRP caused half-maximal effect at 2 nM, and were threefold more potent than human CGRP. CGRP-stimulated amylase release was not inhibited by VIP-(10-28) or secretin-(5-27). CGRP stimulated cAMP and was augmented by phosphodiesterase inhibitors with the order of sensitivity being Ro-20-1724 greater than isobutylmethylxanthine greater than theophylline. CGRP did not increase 45Ca outflux or effect of 125I-VIP binding. CGRP specifically inhibited 125I-CGRP binding. The dose-response curves were broad and each peptide accelerated dissociation of bound 125I-CGRP. Computer analysis demonstrated two classes of CGRP-binding sites. Occupation of a high-affinity class (Kd 20 nM) correlated with stimulation of enzyme secretion and cAMP, and occupation of the low-affinity class (Kd 1 microM) correlated with accelerated dissociation. These studies demonstrate that CGRP interacts with specific pancreatic receptors, CGRP-stimulated cAMP is in a different compartment from that stimulated by other secretagogues, and CGRP differs from other agents that increase cAMP and amylase release in the relationship among receptor occupation, cAMP generation, and enzyme secretion.