INHIBITION OF PARIETAL-CELL ACID-SECRETION IS MEDIATED BY THE CLASSICAL EPIDERMAL GROWTH-FACTOR RECEPTOR

Epidermal growth factor (EGF) and transforming growth factor-alpha (TG F-alpha) inhibit gastric acid secretion both in vivo and in vitro. Pre vious studies have indicated that EGF and TGF-alpha bind to the same E GF/TGF-alpha receptor. Nevertheless, we and others have previously dem onstrated that inhibition of acid secretion by these growth factors re quires concentrations of the peptides that are 10-fold higher than tho se necessary for induction of mitogenesis. Therefore, we have sought t o investigate whether gastric parietal cells may possess a second EGF/ TGF-alpha receptor class. Two systems were studied: First, [I-125]TGF- alpha was cross-linked to the receptor in isolated rabbit parietal cel l membranes, and labeled species were resolved on SDS-PAGE. Second, ac id secretion was evaluated in pylorus-ligated waved-2 mutant mice, whi ch carry a disabling point mutation in their classical EGF/TGF-alpha r eceptor. In isolated parietal cells, [I-125]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 in hibition of acid secretion by EGF with an IC50 of 20 mu g/kg. In contr ast, EGF had no inhibitory effect on acid secretion in waved-2 mice at concentrations up to 100 mu g/kg. No alterations in parietal cell or gastrin cell numbers were observed. These results in both isolated rab bit parietal cells and waved-2 mice support the existence of only a si ngle class of EGF/TGF-alpha receptors in parietal cells. Differences i n growth factor affinity are likely due to the modification of the rec eptor or one of its coordinate regulators.