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 (TGFalpha) which functions as a potent inhibitor of acid secretion. We have previously demonstrated that TGFalpha can inhibit aminopyrine uptake in isolated rabbit parietal cells. In this study, we have evaluated the components of TGFalpha structure which determine its ability to inhibit parietal cell function. Both human and rat TGFalpha inhibited histamine stimulation by increasing the EC50 for agonist stimulation. Three fragments containing the third loop domain of TGFalpha (rat TGFalpha34-43, human TGFalpha34-43 and human TGFalpha34-50) all inhibited histamine stimulation with IC50 values 20, 33 and 4-fold higher, respectively, than that of the native molecule. Rat TGFalpha inhibited carbachol stimulation throughout an agonist dose response. Human TGFalpha 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 TGFalpha 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 TGFalpha, 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 TGFalpha-mediated inhibition of histamine and carbachol. In addition, in contrast with previous investigations on the mitogenic action of TGFalpha, third loop fragments of TGFalpha retain the capacity to inhibit aminopyrine accumulation.