Inhibition of Parietal Cell Acid Secretion Is Mediated by the Classical Epidermal Growth Factor Receptor VIRENDRA JOSHI, GREGORY S. RAY, and JAMES R. GOLDENRING, MD, PhD Epidermal growth factor (EGF) and transforming growth factor- a (TGF-a) inhibit gastric acid secretion both in vivo and in vitro. Previous studies have indicated that EGF and TGF- a bind to the same EGF/TGF- a 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-a receptor class. Two systems were studied: First, [ 125 I]TGF- a 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-a receptor. In isolated parietal cells, [ 125 I]TGF- a was cross-linked into a single species of 170 kDa. Cross-linking was inhibited in the presence of unlabeled TGF-a with an IC 50 of 80 nM. In the pylorus-ligated mice, control littermate mice demonstrated a dose-dependent inhibition of acid secretion by EGF with an IC 50 of 20 mg/kg. In contrast, EGF had no inhibitory effect on acid secretion in waved-2 mice at concentrations up to 100 mg/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-a receptors in parietal cells. Differences in growth factor af®nity are likely due to the modi®cation of the receptor or one of its coordinate regulators. KEY WORDS: epidermal growth factor; parietal cells; acid secretion. Epidermal growth factor (EGF) and transforming growth factor (TGF-a) are homologous polypeptides (1± 4) that are representative of a family of related growth factor peptides that also includes amphiregul- lin and heparin-binding EGF (5). The predominance of data suggests that all of these ligands bind to the same EGF/TGF- a receptor (5). Both EGF and TGF-a have important physiological roles in gastric mucosal growth (6), repair (7±9), and acid secretion (10 ±13). The spectrum of biological activities of EGF and TGF-a are similar, but qualitative differences have been observed (4, 5, 8, 14). When EGF is bound to the receptor, the complex is internalized and de- graded, whereas when TGF-a is bound, the receptor is rapidly recycled (14). We and others have previ- ously reported that both EGF (10, 12, 15) and TGF- a (11, 16) inhibit acid secretion. In gastric parietal cells, the pharmacology and pattern of second messenger activation by both EGF and TGF- a are identical (12, 16). In addition, inhibitors of tyrosine kinases block the acid inhibitory action of the growth factors (17). Manuscript received January 23, 1997; accepted March 13, 1997. From the Augusta Veterans Affairs Medical Center and the Institute for Molecular Medicine and Genetics, Departments of Medicine, Surgery and Cellular Biology & Anatomy, Medical Col- lege of Georgia, Augusta, Georgia 30912. Address for reprint requests: Dr. James R. Goldenring, Institute for Molecular Medicine and Genetics, CB-2803, Medical College of Georgia, 1120 Fifteenth Street, Augusta, Georgia 30912-3175. Digestive Diseases and Sciences, Vol. 42, No. 6 (June 1997), pp. 1194±1198 1194 Digestive Diseases and Sciences, Vol. 42, No. 6 (June 1997) 0163-2116/97/0600-1194$12.50/0 Ñ 1997 Plenum Publishing Corporation