G protein-coupled cholecystokinin-B/gastrin receptors are responsible for physiological cell growth of the stomach mucosa in vivo.
Many peptide hormone and neurotransmitter receptors belonging to the seven membrane-spanning G protein-coupled receptor family have been shown to transmit ligand-dependent mitogenic signals in vitro. However, the physiological roles of the mitogenic activity through G protein-coupled 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 atrophy of the gastric mucosa macroscopically, even in the presence of severe hypergastrinemia. The atrophy was due to a decrease in parietal cells and chromogranin A-positive enterochromaffin-like cells expressing the H+,K(+)-ATPase and histidine decarboxylase genes, respectively. Oral administration of a proton pump inhibitor, omeprazole, which induced hypertrophy of the gastric mucosa with hypergastrinemia in wild-type littermates, did not eliminate the gastric atrophy of the homozygotes. These results clearly demonstrated that the G protein-coupled CCK-B/gastrin receptor is essential for the physiological as well as pathological proliferation of gastric mucosal cells in vivo.
Nagata
A
A
Department of Medicine, Kobe University School of Medicine, Japan.
Ito
M
M
Iwata
N
N
Kuno
J
J
Takano
H
H
Minowa
O
O
Chihara
K
K
Matsui
T
T
Noda
T
T
D000818:Animals; D001284:Atrophy; D019439:Chromaffin Cells / Q000502:physiology; D053379:Chromogranin A; D002864:Chromogranins / Q000032:analysis / Q000502:physiology; D015342:DNA Probes; D005753:Gastric Mucosa / Q000166:cytology* / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D005755:Gastrins / Q000378:metabolism; D015870:Gene Expression; D015698:Genomic Library; D017506:H(+)-K(+)-Exchanging ATPase / Q000096:biosynthesis; D006640:Histidine Decarboxylase / Q000096:biosynthesis; D006720:Homozygote; D006801:Humans; D006984:Hypertrophy; D051379:Mice; D018345:Mice, Knockout; D009853:Omeprazole / Q000494:pharmacology; D010295:Parietal Cells, Gastric / Q000473:pathology / Q000502:physiology; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D012844:Sincalide / Q000378:metabolism
D053379:Chromogranin A; D002864:Chromogranins; D015342:DNA Probes; D005755:Gastrins; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D017506:H(+)-K(+)-Exchanging ATPase; D006640:Histidine Decarboxylase; D009853:Omeprazole; D012844:Sincalide