AJP - Gastrointestinal and Liver Physiology, Vol 251, Issue 3 391-G397, Copyright © 1986 by American Physiological Society
Mechanism of action of calcitonin gene-related peptide in stimulating pancreatic enzyme secretion
Z. C. Zhou, M. L. Villanueva, M. Noguchi, S. W. Jones, J. D. Gardner and R. T. Jensen
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.
