Abstract
To find mammalian analogues of exendin-4, a peptide from Helodermatidae venoms that interacts with newly discovered exendin receptors on dispersed acini from guinea pig pancreas, we examined the actions of recent additions to the vasoactive intestinal peptide/secretin/glucagon family of regulatory peptides. In every respect tested, the truncated form of glucagon-like peptide-1, GLP-1(7-36)NH2, mimicked the actions of exendin-4. Like exendin-4, GLP-1(7-36)NH2 caused an increase in acinar cAMP without stimulating amylase release. GLP-1(7-36)NH2-induced increases in cAMP were inhibited progressively by increasing concentrations of the specific exendin-receptor antagonist, exendin(9-39)NH2. In dispersed acini from guinea pig and rat pancreas, concentrations of GLP-1(7-36)NH2 that stimulated increases in cAMP caused potentiation of cholecystokinin-induced amylase release. Binding of 125I-[Y39]exendin-4 or 125I-GLP-1(7-36)NH2 to dispersed acini from guinea pig pancreas was inhibited by adding increasing concentrations of unlabeled exendin-4 or GLP-1(7-36)NH2. We conclude that the mammalian peptide GLP-1(7-36)NH2 interacts with exendin receptors on dispersed acini from guinea pig pancreas. Exendin(9-39)NH2, a competitive antagonist of the actions of GLP-1(7-36)NH2 in pancreatic acini, may be a useful tool for examining the physiological actions of this peptide.
Highlights
From the $Departmentof Medicine, Division of Digestive Diseases, State Universityof New York-HealthScience Center, Brooklyn, New York 11203-2098 and the Wolomon A
To study further the effects of exendin(9-39)NH2 on the increase in cAMPcaused by GLP-l(7-36)NH2, we examined plus GLP-l(7-36)NH2 did not result in potentiation of amylase release from dispersed acini prepared from rat pancreas (15,16).T o determine whether thdeiscrepancy betweenthese reports and our observations in pancreatic acinfriom guinea pig pancreas was caused by species differences, we repeated the same experiment shown in Fig. 4 ( l e f t )using dispersed acini prepared from rat pancreas (Fig. 5 )
Our findings indicate that the mammalian peptide GLP1(7-36)NHzinteracts withexendinreceptorson dispersed acinifromguinea pig pancreas to increasecellularCAMP
Summary
Oreny1)methoxycarbonyl aminoacids onaMilligen 9050 peptide synthesizer (Milligen, Burlington, MA). Whereas adding 1p M exendin(9-39)NH2 did not alter the increase in cAMP caused by secretin, VIP, or PACAP-38, the fragment abolished the actions of exendin-4 and GLP-1(7-36)NH2. These results suggest that the actionsof GLP-1(7-36)NH2, but not PACAP-38, are mediated by interaction with exendin recep-. In eachexperimenteach valuewas determinedinduplicate,and tration of CCK-8 that caused maximal enzyme release, 0.3 results are means f S.E. from four separate experiments.
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