Transforming growth factor-alpha (TGF alpha) inhibition of parietal cell secretion: structural requirements for activity.

Parietal cells of the gastric fundus produce transforming growth factor-alpha (TGF alpha) which functions as a potent inhibitor of acid secretion. We have previously demonstrated that TGF alpha can inhibit aminopyrine uptake in isolated rabbit parietal cells. In this study, we have evaluated the components of TGF alpha structure which determine its ability to inhibit parietal cell function. Both human and rat TGF alpha inhibited histamine stimulation by increasing the EC50 for agonist stimulation. Three fragments containing the third loop domain of TGF alpha (rat TGF alpha 34-43, human TGF alpha 34-43 and human TGF alpha 34-50) all inhibited histamine stimulation with IC50 values 20, 33 and 4-fold higher, respectively, than that of the native molecule. Rat TGF alpha inhibited carbachol stimulation throughout an agonist dose response. Human TGF alpha was only effective in inhibiting carbachol if incubations were performed in the presence of air rather than 100% O2. In air incubation, all three of the TGF alpha fragments inhibited carbachol stimulation but, in contrast to the effects on histamine, the peptides all were virtually equipotent with the native molecule. The human sequence fragments, like the native human TGF alpha, elicited no inhibition when incubations were performed in the presence of 100% O2. The results suggest that there are pharmacological differences in the response of isolated parietal cells to TGF alpha-mediated inhibition of histamine and carbachol. In addition, in contrast with previous investigations on the mitogenic action of TGF alpha, third loop fragments of TGF alpha retain the capacity to inhibit aminopyrine accumulation.