G protein-coupled cholecystokinin-B/gastrin receptors are responsible for physiological cell growth of the stomach mucosa in vivo.

Abstract

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.Cell proliferation and differentiation are regulated by a wide array of factors such as growth factors, cytokines, and hormones (1). Several peptide hormones such as bombesin/ gastrin-releasing peptide, angiotensin, and endothelin, and neurotransmitters such as serotonin and adrenaline have been shown to stimulate cell proliferation through their own seventransmembrane, heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors in vitro (2-5). Certain serotonin, acetylcholine, or adrenergic receptor subtypes were reported not only to stimulate cell proliferation but also to transform 3T3 fibroblasts in a ligand-dependent manner as do growth factor receptors (3-5). Very recently, G proteincoupled receptors have also been shown to involve tyrosine kinases and the Ras-mitogen-activating protein kinase pathway in their intracellular signaling as do growth factor and cytokine receptors (6-9). Although some peptides could promote the proliferation of a variety of human tumor cell lines in vivo as well as in vitro (10,11), the physiological significance of the mitogenic activity through the G protein-coupled receptor superfamily remains to be clarified.The peptide hormone, gastrin, is well characterized as a stimulant of gastric acid secretion. In addition, there is circumstantial evidence that gastrin presumably functions as a trophic factor for the gastrointestinal tissues (11, 12). Another peptide hormone, cholecystokinin (CCK), is also isolated as a stimulant of enzyme secretion by the pancreas (13). Because of the abundant expression of CCK in the central nervous system as well as in digestive organs, this hormone is also thought to act as a neurotransmitter or modulator in the brain (14). Moreover, the specific receptors for CCK and/or gastrin have been pharmacologically shown to be expressed in various human tumor cells and to stimulat...

Gastrin stimulates the growth of gastric pit cell precursors by inducing its own receptors

“…An amplified 155-bp DNA fragment underwent direct DNA sequencing for confirmation using Receptor binding study. To perform the in vitro gastrin binding experiment, we isolated the membrane fraction from GSM06 cells preincubated in the presence or absence of various peptides for 2 days at 33°C by homogenization and centrifugation at 42,000 g for 15 min as reported previously (27). The membrane fraction (1 mg) was labeled for 2 h at 24°C with 50 pM [ 125 I]gastrin in the presence of varying concentrations (10 Ϫ11 to 10 Ϫ6 M) of nonlabeled gastrin, CCK-8, or G-Gly.…”

“…CCKA-Rs exhibit a 500-to 1,000-fold higher affinity for sulfated analogs of CCK than for gastrin, whereas CCKB-Rs have approximately equal affinity for both sulfated and non-sulfated peptide analogs of CCK and gastrin (32,34,46,47). CCKB-Rs are present in parietal, ECL, and probably somatostatin cells (2,4,23,27,28,41 (2,28). Immunohistochemical studies have also demonstrated the distribution of CCKB-R in the same cell types (41).…”

Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma

“…Mice that lack the gastrin gene or the gastrin/ cholecystokinin-B receptor have altered gastric mucosal architecture and differentiation (Nagata et al, 1996;Koh et al, 1997;Friis-Hansen et al, 1998). Gastrin and gastrin receptor-null mice exhibit reduced numbers of enterochromaffin-like cells and an expansion of mucous and surface epithelial cells (Nagata et al, 1996;Koh et al, 1997;Friis-Hansen et al, 1998).…”

SH3 Binding Domains in the Dopamine D4 Receptor

“…Gi-mediated GPCRs, were shown to produce a mitogenic response which was blocked by the tyrosine A recent study has shown, using gene knock-out studies, that certain GPCRs are essential for ce11 growth under physiologicd conditions (Nagata et al, 1996). Activation of GPCRs l a d s to rapid phosphorylation and activation of MAP kinases.…”