High potency antagonists of the pancreatic glucagon-like peptide-1 receptor

Chahrzad Montrose-Rafizadeh, Huan Yang, Buel D. Rodgers, Alvie Beday, Louella A. Pritchette, John Eng

Research output: Contribution to journalArticlepeer-review

152 Scopus citations

Abstract

GLP-1-(7-36)-amide and exendin-4-(1-39) are glucagon-like peptide-1 (GLP-1) receptor agonists, whereas exendin-(9-39) is the only known antagonist. To analyze the transition from agonist to antagonist and to identify the amino acid residues involved in ligand activation of the GLP-1 receptor, we used exendin analogs with successive N-terminal truncations. Chinese hamster ovary cells stably transfected with the rat GLP-1 receptor were assayed for changes in intracellular cAMP caused by the test peptides in the absence or presence of half-maximal stimulatory doses of GLP-1. N- terminal truncation of a single amino acid reduced the agonist activity of the exendin peptide, whereas N-terminal truncation of 3-7 amino acids produced antagonists that were 4-10 fold more potent than exendin-(9-39). N- terminal truncation of GLP-1 by 2 amino acids resulted in weak agonist activity, but an 8-amino acid N-terminal truncation inactivated the peptide. Binding studies performed using 125I-labeled GLP-1 confirmed that all bioactive peptides specifically displaced tracer with high potency. In a set of exendin/GLP-1 chimeric peptides, substitution of GLP-1 sequences into exendin-(3-39) produced loss of antagonist activity with conversion to a weak agonist. The results show that receptor binding and activation occur in separate domains of exendin, but they are more closely coupled in GLP-1.

Original languageEnglish
Pages (from-to)21201-21206
Number of pages6
JournalJournal of Biological Chemistry
Volume272
Issue number34
DOIs
StatePublished - 22 Aug 1997

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