Inhibition of parietal cell acid secretion is mediated by the classical epidermal growth factor receptor

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) inhibit gastric acid secretion both in vivo and in vitro. Previous studies have indicated that EGF and TGF-alpha bind to the same EGF/TGF-alpha receptor. Nevertheless, we and others have previously demonstrated that inhibition of acid secretion by these growth factors requires concentrations of the peptides that are 10-fold higher than those necessary for induction of mitogenesis. Therefore, we have sought to investigate whether gastric parietal cells may possess a second EGF/TGF-alpha receptor class. Two systems were studied: First, [125I]TGF-alpha was cross-linked to the receptor in isolated rabbit parietal cell membranes, and labeled species were resolved on SDS-PAGE. Second, acid secretion was evaluated in pylorus-ligated waved-2 mutant mice, which carry a disabling point mutation in their classical EGF/TGF-alpha receptor. In isolated parietal cells, [125I]TGF-alpha was cross-linked into a single species of 170 kDa. Cross-linking was inhibited in the presence of unlabeled TGF-alpha with an IC50 of 80 nM. In the pylorus-ligated mice, control littermate mice demonstrated a dose-dependent inhibition of acid secretion by EGF with an IC50 of 20 micrograms/kg. In contrast, EGF had no inhibitory effect on acid secretion in waved-2 mice at concentrations up to 100 micrograms/kg. No alterations in parietal cell or gastrin cell numbers were observed. These results in both isolated rabbit parietal cells and waved-2 mice support the existence of only a single class of EGF/TGF-alpha receptors in parietal cells. Differences in growth factor affinity are likely due to the modification of the receptor or one of its coordinate regulators.