The CCKB/gastrin receptor is coupled to the regulation of enzyme secretion, protein synthesis and p70 S6 kinase activity in acinar cells from ElasCCKB transgenic mice

In order to determine which physiological functions can be regulated by the pancreatic CCKB/gastrin receptor, studies were carried out on pancreatic a cini from mice expressing transgenic CCKB/gastrin receptors in the exocrine pancreas (ElasCCKB mice). Acini were stimulated by sulfated gastrin in the presence of SR 27897 (1.8 mu M), blocking endogenous CCKA receptors. After 30 min incubation with gastrin, the secretion of chymotrypsinogen and amyl ase showed superimposable monophasic dose-response curves. Enzyme secretion was detectable and maximal at 100 pM and 1 nM of gastrin, respectively. No increase in chymotrypsinogen and amylase mRNAs was detected for doses of g astrin which specifically occupy the CCKB/gastrin receptor. In contrast, ga strin stimulated total protein synthesis in isolated acini from ElasCCKB mi ce. [S-35]Methionine incorporation into total proteins was increased dose-d ependently to a maximum for 30 pM gastrin and inhibited with higher doses ( > 300 pM). Gastrin stimulated p70 S6 kinase activity for concentrations ran ging from 10 pM to 1 nM. Gastrin-stimulated p70 S6 kinase activity and prot ein synthesis were blocked by rapamycin and wortmannin. Therefore, in ElasC CKB mice acinar cells, the CCKB/gastrin receptor mediates enzyme release an d protein synthesis. However, a more efficient coupling of the CCKB/gastrin receptor to protein synthesis than to enzyme secretion was demonstrated. C CKB/gastrin receptor-stimulated protein synthesis likely results from an en hancement of mRNA translation and involves phosphatidyl inositol 3-kinase a nd p70 S6 kinase.