G-PROTEIN-COUPLED CHOLECYSTOKININ-B GASTRIN RECEPTORS ARE RESPONSIBLEFOR PHYSIOLOGICAL CELL-GROWTH OF THE STOMACH MUCOSA IN-VIVO/

Many peptide hormone and neurotransmitter receptors belonging to the s even membrane-spanning G protein-coupled receptor family have been sho wn to transmit ligand-dependent mitogenic signals in vitro. However, t he physiological roles of the mitogenic activity through G protein-cou pled receptors in vivo remain to be elucidated. Here we have generated G protein-coupled cholecystokinin (CCK)-B/gastrin receptor deficient- mice by gene targeting. The homozygous mice showed a remarkable atroph y of the gastric mucosa macroscopically, even in the presence of sever e hypergastrinemia. The atrophy was due to a decrease in parietal cell s and chromogranin A-positive enterochromaffin-like cells expressing t he H+,K+-ATPase and histidine decarboxylase genes, respectively. Oral administration of a proton pump inhibitor, omeprazole, which induced h ypertrophy of the gastric mucosa with hypergastrinemia in wild-type li ttermates, did not eliminate the gastric atrophy of the homozygotes. T hese results clearly demonstrated that the G protein-coupled CCK-B/gas trin receptor is essential for the physiological as well as pathologic al proliferation of gastric mucosal cells in vivo.