Abstract
Exendin-4 purified from Heloderma suspectum venom shows structural relationship to the important incretin hormone glucagon-like peptide 1-(7-36)-amide (GLP-1). We demonstrate that exendin-4 and truncated exendin-(9-39)-amide specifically interact with the GLP-1 receptor on insulinoma-derived cells and on lung membranes. Exendin-4 displaced 125I-GLP-1, and unlabeled GLP-1 displaced 125I-exendin-4 from the binding site at rat insulinoma-derived RINm5F cells. Exendin-4 had, like GLP-1, a pronounced effect on intracellular cAMP generation, which was reduced by exendin-(9-39)-amide. When combined, GLP-1 and exendin-4 showed additive action on cAMP. They each competed with the radio-labeled version of the other peptide in cross-linking experiments. The apparent molecular mass of the respective ligand-binding protein complex was 63,000 Da. Exendin-(9-39)-amide abolished the cross-linking of both peptides. Exendin-4, like GLP-1, stimulated dose dependently the glucose-induced insulin secretion in isolated rat islets, and, in mouse insulinoma beta TC-1 cells, both peptides stimulated the proinsulin gene expression at the level of transcription. Exendin-(9-39)-amide reduced these effects. In conclusion, exendin-4 is an agonist and exendin-(9-39)-amide is a specific GLP-1 receptor antagonist.
Highlights
Exendin-4 purifiedfrom Heloderma suspecturn glucagonshow some sequence homology to GLP-1,' these venom shows structural relationship to the important peptides exhibit no interactions with the recently discovered incretinhormone glucagon-like peptide 1-(7-36)amide (GLP-1)
Gut endocrinology faces the dilemma that the classic approach of endocrinology to evaluate the significance of an endocrine organ or system by its removal is not possible
The GLP-1 generating and releasing L-cells belong to the diffuse endocrine system of the gut (28)
Summary
19650-19655,1993 Printed in U.S.A. Exendin-4 Is a HighPotency Agonist and TruncatedExendin-(9-39)amide an Antagonist at the Glucagon-like Peptide 1-(7-36)-amide Receptor of Insulin-secreting ,&Cells*. This peptide is derived from the intestinal posttrans- out whether truncated exendin-(9-39)-amide behaves asa lational proglucagon processing and is a member of an extended family of bioactive peptides, the glucagon-secretinvasoactive intestinal polypeptide family, all of which are closely related one to the other in theairmino acid sequences (3, 5).
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