Several chemical messengers delivered by blood, nerves, and local tissue stores to the fundic mucosa regulate acid secretion.
The aim of this grant has been to identify the receptors on parietal and paracrine cells responsible for stimulatory and inhibitory modulation of acid secretion. This renewal proposal is focused upon direct modulators of parietal cell (PC) function. The major determinants of meal-stimulated acid secretion are digested peptides and amino acids (AA). AA stimulate acid secretion via both release of gastrin and direct effects on the fundic mucosa, the mechanisms of which have not been identified. Our proposal has been catalyzed by preliminary findings that the 3 branched chain AA (BCAA), leucine, valine, and isoleucine, markedly enhance the function of isolated canine PC. Our preliminary data suggest that these BCAA may either be modulators or necessary permissive factors for the canine PC response to other secretagogues. Our overall goal is to learn whether action of these BCAA on PC is physiologically relevant and to define the possible mechanisms by which these substrates induce their function effects. We will study the stereospecificity, dose response, and time course for BCAA stimulation of PC function. We will compare the effects of BCAA on 14C- aminopyrine accumulation, morphological transformation, and oxygen consumption. We will pursue our preliminary finding that depletion of endogenous BCAA depresses the PC response to other secretagogues. We will test the hypothesis that AA transport via the L-system is rate-limiting by utilizing selective inhibitors and competing substrates testing both function and uptake radiolabelled AA. We will compare uptake between highly enriched PC and chief cells to determine if PC BCAA uptake is unique. We will determine if metabolism of BCAA is necessary for BCAA stimulation, comparing metabolic rates with functional responses. We will test the possibility that BCAA enhancement reflects amplification of cell activation signals, studying BCAA effects on cyclic AMP generation, phophotidylinositol breakdown and cytosolic calcium signals alone and in combinations with other stimuli. BCAA effects on the Na+/H+ antiporter will be evaluated as will BCAA effects on protein phosphorylation. These studies will elucidate direct AA effects on PC function and may provide insight into basic mechanisms by which nutrients modulate cell function.
Showing the most recent 10 out of 17 publications
