Biological activity of progastrin posttranslational processing intermediates.

Abstract

We recently identified carboxyl-terminally extended progastrin posttranslational processing intermediates in G cells of the gastric antrum and demonstrated that they are cosecreted with gastrin. To determine the physiological significance of these intermediates, we examined the biological activity of two synthetic gastrin precursor analogues that correspond to hexagastrin with carboxyl-terminal extensions, Tyr-Gly-Trp-Met-Asp-Phe-Gly (GL-7) and Tyr-Gly-Trp-Met-Asp-Phe-Gly-Arg-Arg (GL-9) on gastric parietal and D cells isolated from canine fundic mucosa. Both analogues were as efficacious as gastrin heptadecapeptide in displacing 125I-[Leu15]gastrin from binding sites on the two cell types and in stimulating [14C]aminopyrine uptake by parietal cells and somatostatin release from D cells. However, both analogues were 10(4)- to 10(5)-fold less potent than gastrin heptadecapeptide in these activities. Our results indicate that progastrin processing intermediates do not have physiologically relevant actions under normal circumstances and support the notion that carboxyl-terminally amidated peptides such as gastrin require the amide moiety for biological activity.