Exendin peptides.

Exendin-3 and exendin-4 are biologically active peptides isolated from venoms of the Gila monster lizards, H. horridum and H. suspectum, respectively. They were isolated using a chemical assay which detects peptides with amino-terminal histidine residues. Both are 39 amino acid peptides containing an amino-terminal histidine and a carboxyl-terminal serine amide and are members of the glucagon superfamily of peptide hormones. When tested in a dispersed pancreatic acinar cell assay, exendin-3 stimulates amylase release and with increasing concentrations causes a biphasic increase in cellular cAMP. In contrast, exendin-4 at concentrations up to 1 microM does not stimulate amylase release and produces a monophasic increase in cellular cAMP despite differing from exendin-3 by only two amino acid substitutions at positions 2 and 3 from the N-terminus. Endogenous Mammalian Analog to Exendins? The differences in biological activities can be explained by the observation that exendin-3 interacts with VIP receptors to stimulate amylase release, whereas exendin-4 does not. Both exendin-3 and exendin-4 interact with a putative exendin receptor on pancreatic acinar cells. The presence of this receptor was determined and defined by the ability of a specific inhibitor, exendin(9-39) amide, to abolish the increase in cAMP observed with 0.1-3 nM exendin-3 or exendin-4. The presence of the exendin receptor, although functionally undefined at the present time, predicts the existence of an endogenous mammalian analog to the exendin peptides.